Kras g12c inhibitors and methods of using the same

ABSTRACT

Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional patentapplication 62/438,334 filed on Dec. 22, 2016, which specification ishereby incorporated herein by reference in its entirety for allpurposes.

BACKGROUND

KRAS gene mutations are common in pancreatic cancer, lungadenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer,and bile duct cancer. KRAS mutations are also observed in about 25% ofpatients with NSCLC, and some studies have indicated that KRAS mutationsare a negative prognostic factor in patients with NSCLC. Recently,V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutationshave been found to confer resistance to epidermal growth factor receptor(EGFR) targeted therapies in colorectal cancer; accordingly, themutational status of KRAS can provide important information prior to theprescription of TKI therapy. Taken together, there is a need for newmedical treatments for patients with pancreatic cancer, lungadenocarcinoma, or colorectal cancer, especially those who have beendiagnosed to have such cancers characterized by a KRAS mutation, andincluding those who have progressed after chemotherapy.

SUMMARY

Provided herein are compound having a structure of formula (I)

wherein

E¹ and E² are each independently N or CR¹;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl, C₀₋₃ alkylenearyl,or C₀₋₃ alkyleneheteroaryl, and each R′ is independently H, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl, C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl, or two R′ substituents, together withthe nitrogen atom to which they are attached, form a 3-7-membered ring;

R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R^(4′) is H, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; and

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring,

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein are compounds having a structureof formula (I)

wherein

E¹ and E² are each independently N or CR¹;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₄alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl, or two R′ substituents, together withthe nitrogen atom to which they are attached, form a 3-7-membered ring;

R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₁₄cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

-   -   ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged,        fused, or spiro 6-11 membered ring;    -   L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or        —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene,        —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atom of the        alkylene group can optionally be replaced with O, S, or NH;

R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; and

R⁷ is H or C₁₋₆alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring,

or a pharmaceutically acceptable salt thereof.

Further provided are compounds of formula (II), or a pharmaceuticallyacceptable salt thereof:

wherein E¹ and E² are each independently N or CR¹; J is N, NR¹⁰, orCR¹⁰; M is N, NR¹³, or CR¹³;

is a single or double bond as necessary to give every atom its normalvalence; R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo,C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, andeach R′ is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, orC═NR⁸; R⁸ and R⁹ are each independently H, C₁₋₃alkyl, hydroxy,C₁₋₃alkoxy, cyano, nitro, or C₃₋₆cycloalkyl, or R⁸ and R⁹, takentogether with the carbon atom to which they are attached, can form a 3-6membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl, O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; and

R¹³ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkyleneamine, or C₃₋₁₄cycloalkyl,or a pharmaceutically acceptable salt thereof, with the proviso that

(1) when J is NR¹⁰, M is N or CR¹³;

(2) when M is NR¹³, J is N or CR¹⁰;

(3) when J is CR¹⁰, M is N or NR¹³; and

(4) when M is CR¹³, J is N or NR¹⁰.

In some embodiments, when Q is C═O, and E¹ and E² are each CR¹; theneither (1) R¹⁰ is C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₁₋₃alkylene-C₂₋₇heterocycloalkyl, or halo;or (2) R¹³ is C₁₋₃haloalkyl or C₃₋₅cycloalkyl. In various embodiments, Jis NR¹⁰ and M is CR¹³. In some embodiments, J is CR¹⁰ and M is NR¹³. Insome embodiments, J is N and M is NR¹³. In various embodiments, J isNR¹⁰ and M is N.

Further provided are compounds having a structure of formula (II)

wherein

E¹ and E² are each independently N or CR¹;

J is N, NR¹⁰, or CR¹⁰;

M is N, NR¹³, or CR¹³;

is a single or double bond as necessary to give every atom its normalvalence;

R¹ is independently H, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring;

Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, or C═NR⁸;

R⁸ and R⁹ are each independently H, C₁₋₃alkyl, hydroxy, C₁₋₃alkoxy,cyano, nitro, or C₃₋₆cycloalkyl, or R⁸ and R⁹, taken together with thecarbon atom to which they are attached, can form a 3-6 membered ring;

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine;

with the proviso that

-   -   (1) when J is NR¹⁰, M is N or CR¹³;    -   (2) when M is NR¹³, J is N or CR¹⁰;    -   (3) when J is CR¹⁰, M is N or NR¹³; and    -   (4) when M is CR¹³, J is N or NR¹⁰.

In some embodiments, when Q is C═O, and E¹ and E² are each CR¹; theneither (1) R¹⁰ is C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₁₋₃alkylene-C₂₋₇heterocycloalkyl, or halo;or (2) R¹³ is C₁₋₃haloalkyl or C₃₋₅cycloalkyl. In various embodiments, Jis NR¹⁰ and M is CR¹³. In some embodiments, J is CR¹⁰ and M is NR¹³. Insome embodiments, J is N and M is NR¹³. In various embodiments, J isNR¹⁰ and M is N.

Further provided are compounds of formula (III) or (III′), or apharmaceutically acceptable salt thereof:

wherein E¹ and E² are each independently N or CR¹;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃ alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring;

Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, or C═NR⁸;

R⁸ and R⁹ are each independently H, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy,cyano, nitro, or C₃₋₁₄cycloalkyl, or R⁸ and R⁹, taken together with thecarbon atom to which they are attached, can form a 3-6 membered ring;

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine.

Further provided are compounds of formula (III) or (III′), or apharmaceutically acceptable salt thereof:

wherein

E¹ and E² are each independently N or CR¹;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃ alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl;R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring;

Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, or C═NR⁸;

R⁸ and R⁹ are each independently H, C₁₋₆alkyl, hydroxy, C₁₋₆alkoxy,cyano, nitro, or C₃₋₁₄cycloalkyl, or R⁸ and R⁹, taken together with thecarbon atom to which they are attached, can form a 3-6 membered ring;

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine.

In some embodiments, the compounds have a structure of formula (III). Inother embodiments, the compounds have a structure of formula (III′).

The compounds of formula (II) or (III) as disclosed herein can have oneor more of the following features. In some embodiments, Q is C═O. Insome embodiments, Q is C═S. In some embodiments, Q is C═NR⁸. In variousembodiments, R⁸ is C₁₋₂alkyl. In some embodiments, Q is CR⁸R⁹. Invarious embodiments, Q is C═CR⁸R⁹. In some embodiments, R⁸ and R⁹, takentogether with the carbon atom to which they are attached, form a 3-4membered ring. In some embodiments, R⁸ is C₁₋₂alkyl, and R⁹ is H.

Also provided are compounds of formula (IV) or (IV′), or apharmaceutically acceptable salt thereof:

E¹ and E² are each independently CR¹ or N;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅alkylene, one carbon atom of the alkylene group can optionally bereplaced with O, S, or NH;

R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring;

R⁸ is H, C₁₋₃alkyl, hydroxy, C₁₋₃alkoxy, halo, cyano, nitro, C₃₋₁₄cycloalkyl, or NR¹¹R¹²;

R¹¹ and R¹² are each independently H, C₁₋₈alkyl, or C₃₋₁₄cycloalkyl; and

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₂₋₁₄heteroaryl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₂₋₁₄heteroaryl,O—C₀₋₃alkylene-C₃₋₁₄ cycloalkyl, O—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, N—C₀₋₃alkylene-C₃₋₁₄ cycloalkyl,N—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, or C₁₋₆alkylene-amine;

In some embodiments, the compounds disclosed herein have a structure offormula (IV). In various embodiments, the compounds disclosed hereinhave a structure of formula (IV′). In some embodiments, E¹ and E² areeach CR¹, and R⁸ is hydroxy, halo, nitro, or C₃₋₆cycloalkyl.

In some embodiments, R⁸ is methyl.

Further provided are compounds having a structure of formula (IV) or(IV′):

wherein

E¹ and E² are each independently CR¹ or N;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₁₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring;

R⁸ is H, C₁₋₃alkyl, hydroxy, C₁₋₃alkoxy, halo, cyano, nitro, C₃₋₁₄cycloalkyl, or NR¹¹R¹²;

R¹¹ and R¹² are each independently H, C₁₋₈alkyl, or C₃₋₁₅cycloalkyl; and

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds disclosed herein have a structure offormula (IV). In various embodiments, the compounds disclosed hereinhave a structure of formula (IV′). In some embodiments, E¹ and E² areeach CR¹, and R⁸ is hydroxy, halo, nitro, or C₃₋₆cycloalkyl.

In some embodiments, R⁸ is methyl.

Further provided are compounds having a structure of formula (V), or apharmaceutically acceptable salt thereof:

wherein

E¹ and E² are each independently CR¹ or N;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₃₋₁₄cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂₋₅alkylene, andNH—C₂₋₅ alkylene, one carbon atom of the alkylene group can optionallybe replaced with O, S, or NH;

R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring; and

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.

Further provided are compounds having a structure of formula (V):

wherein

E¹ and E² are each independently CR¹ or N;

R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,NH—C₁₋₆alkyl, N(C₁₋₆alkyl)₂, cyano, or halo;

R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl,C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring;

R³ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₃₋₁₄cycloalkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, or heteroaryl;

R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring;

L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₆alkylene, or—NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene,—S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atom of the alkylenegroup can optionally be replaced with O, S, or NH;

R⁵ and R⁶ are each independently H, halo, C₁₋₆-alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring;

R⁷ is H or C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to whichthey are attached, form a 4-6 membered ring; and

R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, or C₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Insome embodiments, each of E¹ and E² is CR¹. In other embodiments, E¹ isCR¹ and E² is N. In some embodiments, E¹ is N and E² is CR¹. In variousembodiments, each of E¹ and E² is N.

The compounds of formula (II), (III), (III′), (IV), (IV′), or (V) asdisclosed herein can have one or more of the following features. Invarious embodiments, R¹⁰ is C₁₋₆alkyl, aryl, heteroaryl,C₃₋₁₄cycloalkyl, C₂₋₁₄ heterocycloalkyl, C₁₋₆alkoxy,O—C₀₋₆alkylene-C₆₋₁₄aryl, O—C₀₋₆alkylene-C₂₋₁₄ heteroaryl,O—C₀₋₆alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₆alkylene-C₂₋₁₄heterocycloalkyl,N—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₆alkylene-C₆₋₁₄aryl,NH—C₀₋₆alkylene-C₂₋₁₄ heteroaryl, NH—C₀₋₆alkylene-C₃₋₁₄cycloalkyl, orNH—C₀₋₆alkylene-C₂₋₁₄ heterocycloalkyl. In various embodiments, R¹⁰ isC₁₋₈alkyl. In some embodiments, R¹⁰ is C₀₋₃alkylene-C₆₋₁₄aryl. In someembodiments, R¹⁰ is C₀₋₃ alkylene-C₂₋₁₄heteroaryl. In some embodiments,R¹⁰ is C₀₋₃alkylene-C₃₋₁₄ cycloalkyl. In some embodiments, R¹⁰ isC₀₋₃alkylene-C₂₋₁₄heterocycloalkyl. In other embodiments, R¹⁰ isC₀₋₆alkyleneamine. For example, R¹⁰ can be i-Pr, t-Bu, phenyl, benzyl,OCH₃, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

In some embodiments, R¹⁰ comprises an ortho-substituted aryl,ortho-substituted heteroaryl, or 2-substituted cyclohexyl. For example,R¹⁰ can be

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Insome embodiments, R¹ is H. In some embodiments, R¹ is F. In someembodiments, R¹ is methyl.

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Invarious embodiments, R² is aryl. In some embodiments, R² is heteroaryl.In various embodiments, R² is phenyl, naphthyl, pyridyl, indazolyl,indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl,imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl,isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl,isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, ortetrahydroisoquinolinyl. For example, R² can be Cl, Br, CF₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine,pyrrolidine, azetidine, OCH₃, OCH₂CH₃, phenyl,

In various embodiments, R² can be bromine,

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Invarious embodiments, R³ is halo. In various embodiments, R³ is Cl. Insome embodiments, R³ is C₁₋₂alkyl. In some embodiments, R³ is methyl. Insome embodiments, R³ is C₁₋₂haloalkyl. In various embodiments, R³ isCF₃.

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Insome embodiments, R⁴ is

In various embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ can be

In various embodiments R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₀₋₃alkylene-C₂₋₇heterocycloalkyl,C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

In various embodiments,

In some embodiments, ring A is

or In some embodiments, ring A comprises piperidinyl, piperazinyl,pyrrolidinyl, or azetidinyl. In some embodiments, ring A comprisespiperidinyl. In various embodiments, ring A can be

In various embodiments, ring A can be

The compounds of formula (I), (II), (III), (III′), (IV), (IV′), or (V)as disclosed herein can have one or more of the following features. Insome embodiments, L is a bond. In some embodiments, L is C₁₋₂alkylene.In various embodiments, L is O. In some embodiments, L is S. In variousembodiments, L is NH. In some embodiments, R⁵ is H or halo. In someembodiments, R⁵ is H, Br, Cl, F, CN, CH₃, CF₃, CH₂Br, CH₂OH, CH₂CH₂OH,CH₂OCH₂phenyl, cyclopropyl, phenyl, CH₂phenyl, CH₂OCH₃, CH₂N(CH₃)₂,CH₂N(CH₂CH₃)₂, CH₂CO₂H, CH₂CO₂CH₃, CH₂NHC(O)CH₃, CH₂C(O)NHCH₃,CH₂OC(O)CH₃, or

In some embodiments, R⁶ is C₁₋₆alkyl, C₁₋₆alkylene-O—C₁₋₆alkyl,C₁₋₆alkylene-OH, C₁₋₃haloalkyl, C₁₋₆alkylene-amine, C₀₋₆alkylene-amide,C₀₋₁alkylene C(O)OC₁₋₃alkyl, C₀₋₁alkylene-C₂₋₁₄heterocycloalkyl,C₀₋₁alkylene-C₃₋₁₄cycloalkyl, or C₀₋₃alkylene-C₆₋₁₄aryl. In variousembodiments, R⁶ is C₀₋₆alkylene-amine or C₀₋₃alkylene-amide and isCH₂NH₂, CH(CH₃)NH₂, CH(CH₃)₂NH₂, CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂, CH₂NHCH₃,C(O)NHCH₃, C(O)N(CH₃)₂, CH₂C(O)NHphenyl, CH₂NHC(O)CH₃, CH₂NHCH₂CH₂OH,CH₂NHCH₂CO₂H, CH₂NH(CH₃)CH₂CO₂CH₃, CH₂NHCH₂CH₂OCH₃,CH₂NH(CH₃)CH₂CH₂OCH₃, CH₂NH(CH₃)CH₂C(O)N(CH₃)₂, CH₂NH(CH₃)CH₂C(O)NHCH₃,CH₂NMe₂, CH₂NH(CH₃)CH₂CH₂OH, CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃,CH₂NHCH₂CHF₂, CH₂NHCH₂CH₃,

In various embodiments, R⁶ is phenyl, cyclopropyl, CH₃, CF₃, CH₂CH₃,CH₂NH₂, CH(CH₃)NH₂, CH(CH₃)₂NH₂, CH₂C₁, CH₂Br, CH₂OCH₃, CH₂Ophenyl,CH₂OH, CO₂H, CO₂CH₂CH₃, CH₂CO₂H, CH₂CH₂NH₂, CH₂CH₂OH, CH₂CH₂N(CH₃)₂,CH₂NHCH₃, C(O)NHCH₃, C(O)N(CH₃)₂, CH₂C(O)NHphenyl, CH₂CHF₂, CH₂F, CHF₂,CH₂NHC(O)CH₃, CH₂NHCH₂CH₂OH, CH₂NHCH₂CO₂H, CH₂NH(CH₃)CH₂CO₂CH₃,CH₂NHCH₂CH₂OCH₃, CH₂NH(CH₃)CH₂CH₂OCH₃, CH₂NH(CH₃)CH₂C(O)N(CH₃)₂,CH₂NH(CH₃)CH₂C(O)NHCH₃, CH₂CH₂CCH, CH₂NMe₂, CH₂NH(CH₃)CH₂CH₂OH,CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃, CH₂NHCH₂CHF₂, CH₂NHCH₂CH₃,

In various embodiments, R⁵ and R⁶ together are

In some embodiments, each of R⁵ and R⁶ is H. In some embodiments, R⁷ isH. In some embodiments, R⁷ is methyl. In various embodiments, R⁷ and R⁵together are —CH₂— or —C(O)CH₂—.

The compounds disclosed herein can be in the form of a pharmaceuticallyacceptable salt. The compounds provided can be formulated into apharmaceutical formulation comprising a compound disclosed herein and apharmaceutically acceptable excipient.

Also provided is a method of inhibiting KRAS G12C in a cell, comprisingcontacting the cell with a compound or composition disclosed herein.Further provided is a method of treating cancer in a subject comprisingadministering to the subject a therapeutically effective amount of acompound or composition disclosed herein. In some embodiments, thecancer is lung cancer, pancreatic cancer, or colorectal cancer.

DETAILED DESCRIPTION Definitions Abbreviations: The FollowingAbbreviations May be Used Herein

AcOH acetic acid aq or aq. Aqueous BOC or Boc tert-butyloxycarbonyl cpmecyclopentyl methyl ether DCE 1,2-dichloroethane DABCO1,4-diazabicyclo[2.2.2]octane DCM Dichloromethane DMAN,N-Dimethylacetamide DMAP 4-dimethylaminopyridine DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxideDppf, DPPF or dppf 1,1′-bis(diphenylphosphino)ferrocene eq or eq. orequiv. Equivalent ESI or ES electrospray ionization Et Ethyl Et₂Odiethyl ether EtOAc ethyl acetate g Grams h Hour HPLC high pressureliquid chromatography iPr Isopropyl iPr₂NEt or DIPEA N-ethyldiisopropylamine (Hünig's base) KHMDS potassium hexamethyldisilazideKOAc potassium acetate Lawesson's reagent2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4- dithiadiphosphetane,2,4-Bis-(4-methoxyphenyl)-1,3- dithia-2,4-diphosphetane 2,4-disulfide LCMS, LCMS, LC-MS or liquid chromatography mass spectroscopy LC/MS LGLeaving group (e.g., halogen, mesylate, triflate) LHMDS or LiHMDSlithium hexamethyldisilazide m/z mass divided by charge Me Methyl MeCNAcetonitrile MeOH Methanol Met Metal species for cross-coupling (e.g.,MgX, ZnX, SnR₃, SiR₃, B(OR)₂) mg Milligrams min Minutes mL MillilitersMS mass spectra NaHMDS sodium hexamethyldisilazide NBSN-bromosuccinimide n-BuLi n-butyllithium NCS N-chlorosuccinimide NMRnuclear magnetic resonance Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂•DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0) PhPhenyl PR or PG or Prot. group protecting group rbf round-bottom flaskRP-HPLC reverse phase high pressure liquid chromatography RT or rt roomtemperature sat. or satd. saturated SFC supercritical fluidchromatography SPhos Pd G3 or SPhos G3(2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate TBAFtetra-n-butylammonium fluoride TBTUN,N,N′N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroboratet-BuOH tert-butanol TEA or Et₃N Trimethylamine TFA trifluoroacetic acidTHF Tetrahydrofuran UV Ultraviolet

The use of the terms “a,” “an,” “the,” and similar referents in thecontext of describing the invention (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated. Recitation of ranges of values herein merelyare intended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended to better illustrate the invention and is not a limitation onthe scope of the invention unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed elementas essential to the practice of the invention.

As used herein, the term “alkyl” refers to straight chained and branchedC1-C₈ hydrocarbon groups, including but not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. The term C_(m-n)means the alkyl group has “m” to “n” carbon atoms. The term “alkylene”refers to an alkyl group having a substituent. An alkyl (e.g., methyl),or alkylene (e.g., —CH₂—), group can be substituted with one or more,and typically one to three, of independently selected, for example,halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano,alkylamino, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —NC, amino, —CO₂H,—CO₂C₁-C₈alkyl, —OCOC₁-C₈alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀heterocycloalkyl, C₅-C₁₀aryl, and C₅-C₁₀ heteroaryl. The term“haloalkyl” specifically refers to an alkyl group wherein at least one,e.g., one to six, or all of the hydrogens of the alkyl group aresubstituted with halo atoms.

The terms “alkenyl” and “alkynyl” indicate an alkyl group that furtherincludes a double bond or a triple bond, respectively.

As used herein, the term “halo” refers to fluoro, chloro, bromo, andiodo. The term “alkoxy” is defined as —OR, wherein R is alkyl.

As used herein, the term “amino” or “amine” interchangeably refers to a—NR₂ group, wherein each R is, e.g., H or a substituent. In someembodiments, the amino group is further substituted to form an ammoniumion, e.g., NR₃ ⁺. Ammonium moieties are specifically included in thedefinition of “amino” or “amine.” Substituents can be, for example, analkyl, alkoxy, cycloalkyl, heterocycloalkyl, amide, or carboxylate. An Rgroup may be further substituted, for example, with one or more, e.g.,one to four, groups selected from halo, cyano, alkenyl, alkynyl, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl,carboxylate, amine, and amide. An “amide” or “amido” groupinterchangeably refers to a group similar to an amine or amino group butfurther including a C(O), e.g., —C(O)NR₂. Some contemplated amino oramido groups (some with optional alkylene groups, e.g., alkylene-amino,or alkylene-amido) include CH₂NH₂, CH(CH₃)NH₂, CH(CH₃)₂NH₂, CH₂CH₂NH₂,CH₂CH₂N(CH₃)₂, CH₂NHCH₃, C(O)NHCH₃, C(O)N(CH₃)₂, CH₂C(O)NHphenyl,CH₂NHC(O)CH₃, CH₂NHCH₂CH₂OH, CH₂NHCH₂CO₂H, CH₂NH(CH₃)CH₂CO₂CH₃,CH₂NHCH₂CH₂OCH₃, CH₂NH(CH₃)CH₂CH₂OCH₃, CH₂NH(CH₃)CH₂C(O)N(CH₃)₂,CH₂NH(CH₃)CH₂C(O)NHCH₃, CH₂CH₂CCH, CH₂NMe₂, CH₂NH(CH₃)CH₂CH₂OH,CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃, CH₂NHCH₂CHF₂, CH₂NHCH₂CH₃,

As used herein, the term “aryl” refers to a C₆₋₁₄ monocyclic orpolycyclic aromatic group, preferably a C₆₋₁₀ monocyclic or bicyclicaromatic group, or C₁₀₋₁₄ polycyclic aromatic group. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, fluorenyl,azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Arylalso refers to C₁₀₋₁₄ bicyclic and tricyclic carbon rings, where onering is aromatic and the others are saturated, partially unsaturated, oraromatic, for example, dihydronaphthyl, indenyl, indanyl, ortetrahydronaphthyl (tetralinyl). Unless otherwise indicated, an arylgroup can be unsubstituted or substituted with one or more, and inparticular one to four, groups independently selected from, for example,halo, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —CF₃, —OCF₃, —NO₂, —CN, —NC,—OH, alkoxy, amino, —CO₂H, —CO₂C₁-C₈alkyl, —OCOC₁-C₈alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ heterocycloalkyl, C₅-C₁₀aryl, and C₅-C₁₀ heteroaryl.

As used herein, the term “cycloalkyl” refers to a monocyclic orpolycyclic non-aromatic carbocyclic ring, where the polycyclic ring canbe fused, bridged, or spiro. The carbocyclic ring can have 3 to 10carbon ring atoms. Contemplated carbocyclic rings include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and cyclononyl.

As used herein, the term “heterocycloalkyl” means a monocyclic orpolycyclic (e.g., bicyclic), saturated or partially unsaturated, ringsystem containing 3 or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7)total atoms, of which one to five (e.g., 1, 2, 3, 4, or 5) of the atomsare independently selected from nitrogen, oxygen, and sulfur.Nonlimiting examples of heterocycloalkyl groups include azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl,thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl,thiacycloheptyl, and diazacycloheptyl.

Unless otherwise indicated, a cycloalkyl or heterocycloalkyl group canbe unsubstituted or substituted with one or more, and in particular oneto four, groups. Some contemplated substituents include halo, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, —OCF₃, —NO₂, —CN, —NC, —OH, alkoxy, amino,—CO₂H, —CO₂C₁-C₈alkyl, —OCOC₁-C₈alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀heterocycloalkyl, C₅-C₁₀aryl, and C₅-C₁₀ heteroaryl.

As used herein, the term “heteroaryl” refers to a monocyclic orpolycyclic ring system (for example, bicyclic) containing one to threearomatic rings and containing one to four (e.g., 1, 2, 3, or 4)heteroatoms selected from nitrogen, oxygen, and sulfur in an aromaticring. In certain embodiments, the heteroaryl group has from 5 to 20,from 5 to 15, from 5 to 10 ring, or from 5 to 7 atoms. Heteroaryl alsorefers to C₁₀₋₁₄ bicyclic and tricyclic rings, where one ring isaromatic and the others are saturated, partially unsaturated, oraromatic. Examples of heteroaryl groups include, but are not limited to,furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl,benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl,benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl,pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quiazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise indicated, aheteroaryl group can be unsubstituted or substituted with one or more,and in particular one to four or one or two, substituents. Contemplatedsubstituents include halo, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —OCF₃,—NO₂, —CN, —NC, —OH, alkoxy, amino, —CO₂H, —CO₂C₁-C₈alkyl,—OCOC₁-C₈alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocycloalkyl, C₅-C₁₀aryl,and C₅-C₁₀ heteroaryl.

As used herein, the term Boc refers to the structure

As used herein, the term Cbz refers to the structure

As used herein, the term Bn refers to the structure

As used herein, the term trifluoroacetamide refers to the structure

As used herein, the term trityl refers to the structure

As used herein, the term tosyl refers to the structure

As used herein, the term Troc refers to the structure

As used herein, the term Teoc refers to the structure

As used herein, the term Alloc refers to the structure

As used herein, the term Fmoc refers to the structure

Compounds of the Disclosure

Provided herein are KRAS inhibitors having structures of one of FormulasI-V, discussed in more detail below.

The compounds disclosed herein include all pharmaceutically acceptableisotopically-labeled compounds wherein one or more atoms of thecompounds disclosed herein are replaced by atoms having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes that can beincorporated into the disclosed compounds include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelled compoundscould be useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action,or binding affinity to pharmacologically important site of action.Certain isotopically-labeled compounds of the disclosure, for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence are preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

Isotopically-labeled compounds as disclosed herein can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying examplesand schemes using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Certain of the compounds as disclosed herein may exist as stereoisomers(i.e., isomers that differ only in the spatial arrangement of atoms)including optical isomers and conformational isomers (or conformers).The compounds disclosed herein include all stereoisomers, both as pureindividual stereoisomer preparations and enriched preparations of each,and both the racemic mixtures of such stereoisomers as well as theindividual diastereomers and enantiomers that may be separated accordingto methods that are known to those skilled in the art. Additionally, thecompounds disclosed herein include all tautomeric forms of thecompounds.

Certain of the compounds disclosed herein may exist as atropisomers,which are conformational stereoisomers that occur when rotation about asingle bond in the molecule is prevented, or greatly slowed, as a resultof steric interactions with other parts of the molecule. The compoundsdisclosed herein include all atropisomers, both as pure individualatropisomer preparations, enriched preparations of each, or anon-specific mixture of each. Where the rotational barrier about thesingle bond is high enough, and interconversion between conformations isslow enough, separation and isolation of the isomeric species may bepermitted.

The disclosure provides a compound having a structure of formula (I)

wherein E¹ and E² are each independently N or CR¹; R¹ is independentlyH, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, NH—C₁₋₄alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, orC₀₋₃alkyleneheteroaryl, and each R′ is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, orheteroaryl, or two R′ substituents, together with the nitrogen atom towhich they are attached, form a 3-7-membered ring; R³ is halo,C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, C₀₋₆alkyleneamide, C₀₋₃alkylene-C(O)OH,C₀₋₃alkylene-C(O)OC₁₋₄alkyl, C₁₋₆alkylene-O-aryl,C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, C₀₋₃alkylene-C₃₈-cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or cyano, or R⁵ andR⁶, together with the atoms to which they are attached, form a 4-6membered ring; and R⁷ is H or C₁₋₃alkyl, or R⁷ and R⁵, together with theatoms to which they are attached, form a 4-6 membered ring, or apharmaceutically acceptable salt thereof.

A compound of formula I, can be in the form of formula (I-A), (I-B),(I-C), or (I-D):

The disclosure also provides a compound having a structure of formula(II)

wherein E¹ and E² are each independently N or CR¹; J is N, NR¹⁰, orCR¹⁰; M is N, NR¹³, or CR¹³;

is a single or double bond as necessary to give every atom its normalvalence; R¹ is independently H, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo,C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₀₋₃alkylene-C₂₋₇heterocycloalkyl,C₀₋₃alkylenearyl, or C₀₋₃alkyleneheteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl, or two R′ substituents, together withthe nitrogen atom to which they are attached, form a 3-7-membered ring;R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or selected from

or R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, C₀₋₆alkyleneamide, C₀₋₃alkylene-C(O)OH,C₀₋₃alkylene-C(O)OC₁₋₄alkyl, C₁₋₆alkylene-O-aryl,C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or cyano, or R⁵ andR⁶, together with the atoms to which they are attached, form a 4-6membered ring; R⁷ is H or C₁₋₃alkyl, or R⁷ and R⁵, together with theatoms to which they are attached, form a 4-6 membered ring; Q is CR⁸R⁹,C═CR⁸R⁹, C═O, C═S, or C═NR⁸; R⁸ and R⁹ are each independently H,C₁₋₃alkyl, hydroxy, C₁₋₃alkoxy, cyano, nitro, or C₃₋₆cycloalkyl, or R⁸and R⁹, taken together with the carbon atom to which they are attached,can form a 3-6 membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylenearyl,C₀₋₃alkyleneheteroaryl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylenearyl,O—C₀₋₃alkyleneheteroaryl, O—C₀₋₃alkylene-C₃₋₈cycloalkyl,O—C₀₋₃alkylenearyl, O—C₀₋₃alkylene-C₂₋₇heterocycloalkyl, NH—C₁₋₈alkyl,N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylenearyl, NH—C₀₋₃alkyleneheteroaryl,NH—C₀₋₃alkylene-C₃₋₈cycloalkyl, NH—C₀₋₃alkylene-C₂₋₇heterocycloalkyl,halo, cyano, or C₁₋₆alkyleneamine; and R¹³ is C₁₋₄alkyl, C₁₋₃haloalkyl,C₁₋₃alkyleneamine, and C₃₋₅cycloalkyl, or a pharmaceutically acceptablesalt thereof, with the proviso that (1) when J is NR¹⁰, M is N or CR¹³;(2) when M is NR¹³, J is N or CR¹⁰; (3) when J is CR¹⁰, M is N or NR¹³;and (4) when M is CR¹³, J is N or NR¹⁰.

In various embodiments, J is NR¹⁰ and M is CR¹³. In some embodiments, Jis CR¹⁰ and M is NR¹³. In some embodiments, J is CR¹⁰ and M is N. Invarious embodiments, J is N and M is NR¹³. In some embodiments, J is Nand M is CR¹³. Some specifically contemplated R¹³ include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, trifluormethyl, CH₂NH₂, andcyclopropyl. In some embodiments, J is NR¹⁰ and M is N. In someembodiments, when Q is C═O and each of E¹ and E² is CR¹, then either (1)R¹⁰ is C₁₋₃alkylenearyl, C₁₋₃alkyleneheteroaryl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₁₋₃alkylene-C₂₋₇heterocycloalkyl, or halo;or (2) R¹³ is C₁₋₃haloalkyl or C₃₋₅cycloalkyl.

A compound of formula II can be in the form of formula (II-A), (II-B),(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-J), (II-K), (II-L),(II-M), (II-N), (II-O), (II-P), or (II-Q):

The disclosure also provides a compound having a structure of formula(III) or formula (III′):

wherein each R¹ is independently H, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo,C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₀₋₃alkylene-C₂₋₇heterocycloalkyl,C₀₋₃alkylenearyl, or C₀₋₃alkyleneheteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl, or two R′ substituents, together withthe nitrogen atom to which they are attached, form a 3-7-membered ring;R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, C₀₋₆alkyleneamide, C₀₋₃alkylene-C(O)OH,C₀₋₃alkylene-C(O)OC₁₋₄alkyl, C₁₋₆alkylene-O-aryl,C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or cyano, or R⁵ andR⁶, together with the atoms to which they are attached, form a 4-6membered ring; R⁷ is H or C₁₋₃alkyl, or R⁷ and R⁵, together with theatoms to which they are attached, form a 4-6 membered ring; Q is CR⁸R⁹,C═CR⁸R⁹, C═O, C═S, or C═NR⁸; each of R⁸ and R⁹ independently is H,C₁₋₃alkyl, hydroxy, C₁₋₃alkoxy, cyano, nitro, or C₃₋₆cycloalklyl, or R⁸and R⁹, taken together with the carbon atom to which they are attached,can form a 3-6 membered ring; and R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylenearyl,C₀₋₃alkyleneheteroaryl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy,O—C₀₋₃alkylenearyl, O—C₀₋₃alkyleneheteroaryl,O—C₀₋₃alkylene-C₃₋₈cycloalkyl, O—C₀₋₃alkylene-C₂₋₇heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylenearyl,NH—C₀₋₃alkyleneheteroaryl, NH—C₀₋₃alkylene-C₃₋₈cycloalkyl,NH—C₀₋₃alkylene-C₂₋₇heterocycloalkyl, halo, cyano, or C₁₋₆alkyleneamine,or a pharmaceutically acceptable salt thereof.

A compound of formula III can be in the form of formula (III-A),(III-B), (III-C), or (III-D):

A compound of formula III′ can be in the form of formula (III-A′),(III-B′), (III-C′), or (III-D′):

The disclosure also provides a compound having a structure of formula(IV) or formula (IV′):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, NH—C₁₋₄alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, orC₀₋₃alkyleneheteroaryl, and each R′ is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, orheteroaryl, or two R′ substituents, together with the nitrogen atom towhich they are attached, form a 3-7-membered ring; R³ is halo,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, C₀₋₆alkyleneamide, C₀₋₃alkylene-C(O)OH,C₀₋₃alkylene-C(O)OC₁₋₄alkyl, C₁₋₆alkylene-O-aryl,C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or cyano, or R⁵ andR⁶, together with the atoms to which they are attached, form a 4-6membered ring; R⁷ is H or C₁₋₃alkyl, or R⁷ and R⁵, together with theatoms to which they are attached, form a 4-6 membered ring; R⁸ isC₁₋₃alkyl, hydroxy, C₁₋₃alkoxy, halo, cyano, nitro, C₃₋₆cycloalkyl, orNR¹¹R¹²; R¹¹ and R¹² are each independently H, C₁₋₄alkyl, orC₃₋₅cycloalkyl; and R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylenearyl,C₀₋₃alkyleneheteroaryl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylenearyl,O—C₀₋₃alkyleneheteroaryl, O—C₀₋₃alkylene-C₃₋₈cycloalkyl,O—C₀₋₃alkylene-C₂₋₇heterocycloalkyl, NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂,NH—C₀₋₃alkylenearyl, NH—C₀₋₃alkyleneheteroaryl,NH—C₀₋₃alkylene-C₃₋₈cycloalkyl, NH—C₀₋₃alkylene-C₂₋₇heterocycloalkyl,halo, cyano, or C₁₋₆alkyleneamine, or a pharmaceutically acceptable saltthereof. In some embodiments, E¹ and E² are each CR¹, and R⁸ is hydroxy,halo, nitro, or C₃₋₆cycloalkyl. In some embodiments, R⁸ is methyl. Thecompound can have a structure of formula (IV-A), (IV′-A), (IV-B),(IV′-B), (IV-C), (IV′-C), (IV-D), or (IV′-D):

Also provided herein are compounds having a structure of formula (V):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, NH—C₁₋₄alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, orC₀₋₃alkyleneheteroaryl, and each R′ is independently H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, orheteroaryl, or two R′ substituents, together with the nitrogen atom towhich they are attached, form a 3-7-membered ring; R³ is halo,C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl,C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, C₀₋₆alkyleneamide, C₀₋₃alkylene-C(O)OH,C₀₋₃alkylene-C(O)OC₁₋₄alkyl, C₁₋₆alkylene-O-aryl,C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₃alkylene-C₂₋₇heterocycloalkyl, C₀₋₃alkylenearyl, or cyano, or R⁵ andR⁶, together with the atoms to which they are attached, form a 4-6membered ring; R⁷ is H or C₁₋₃alkyl, or R⁷ and R⁵, together with theatoms to which they are attached, form a 4-6 membered ring; and R¹⁰ isC₁₋₈alkyl, C₀₋₃alkylenearyl, C₀₋₃alkyleneheteroaryl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₀₋₃alkylene-C₂₋₇heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃alkylenearyl, O—C₀₋₃alkyleneheteroaryl,O—C₀₋₃alkylene-C₃₋₈cycloalkyl, O—C₀₋₃alkylene-C₂₋₇heterocycloalkyl,NH—C₁₋₈alkyl, N—C₁₋₈alkyl, NH—C₀₋₃alkylenearyl,NH—C₀₋₃alkyleneheteroaryl, NH—C₀₋₃alkylene-C₃₋₈cycloalkyl,NH—C₀₋₃alkylene-C₂₋₇heterocycloalkyl, halo, cyano, or C₁₋₆alkyleneamine;or a pharmaceutically acceptable salt thereof.

For Compounds of Formulas (II), (III), and (III′):

In some embodiments, Q is C═O. In some embodiments, Q is C═S. In someembodiments, Q is C═NR⁸. R⁸ can be C₁₋₂alkyl, e.g. methyl.

Q can be CR⁸R⁹ or C═CR⁸R⁹. R⁸ and R⁹, taken together with the carbonatom to which they are attached, can form a 3-4 membered ring, e.g., acyclopropyl ring. In some embodiments, R⁸ is C₁₋₂alkyl (e.g., methyl),and R⁹ is H.

For Compounds of Formulas (II), (III), (III′), (IV), (IV′), and (V):

In various embodiments, R¹⁰ is C₁₋₄alkyl, aryl, heteroaryl,C₃₋₆cycloalkyl, C₃₋₆heterocycloalkyl, C₁₋₄alkoxy, or aryloxy. In variousembodiments, R¹⁰ is C₁₋₈alkyl, C₁₋₈alkyl, or C₁₋₃alkyl. In variousembodiments, R¹⁰ is C₀₋₃alkylenearyl, C₀₋₁alkylenearyl, or phenyl. Invarious embodiments, R¹⁰ is C₀₋₃alkyleneheteroaryl, orC₀₋₁alkyleneheteroaryl, and the heteroaryl can be, e.g., pyridyl. Invarious embodiments, R¹⁰ is C₀₋₃alkylene-C₃₋₈cycloalkyl,C₀₋₁alkylene-C₃₋₈cycloalkyl, or C₃₋₈cycloalkyl, and the cycloalkyl canbe, e.g., cyclohexyl. In various embodiments, R¹⁰ isC₀₋₃alkylene-C₃₋₈heterocycloalkyl or C₀₋₁alkylene-C₃₋₈heterocycloalkyl.In various embodiments, R¹⁰ is C₀₋₆alkyleneamine or C₀₋₃alkyleneamine oramine. Some specifically contemplated R¹⁰ include i-Pr, t-Bu, phenyl,benzyl, OCH₃, Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

R¹⁰ can comprise an ortho-substituted aryl, ortho-substitutedheteroaryl, or 2-substituted cyclohexyl, such as, for example,

For all Compounds:

R¹ can be a small moiety. For example, R¹ can be H, C₁₋₂alkyl (e.g.,methyl), C₁₋₂haloalkyl (e.g., CF₃), or halo (e.g., F). Some specificallycontemplated R¹ include H, F, Me, Cl, and CF₃.

R² can be C₁₋₃alkyl, C₁₋₃haloalkyl, C₁₋₃alkoxy,C₀₋₁alkylene-C₃₋₈cycloalkyl, C₃₋₆cycloalkyl, C₀₋₁alkylenearyl (e.g.,aryl), or C₀₋₁alkyleneheteroaryl (e.g., heteroaryl). Some specificallycontemplated R² groups include phenyl, naphthyl, pyridyl, indazolyl,indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl,imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl,isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl,isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, ortetrahydroisoquinolinyl. Some other specific R² include Cl, Br, CF₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine,pyrrolidine, azetidine, OCH₃, OCH₂CH₃, phenyl,

In some embodiments, R² is

R³ can be halo (e.g., Cl), C₁₋₂alkyl (e.g., methyl), or C₁₋₂haloalkyl(e.g., CF₃). Some specifically contemplated R³ include Cl, Me, CF₃, OMe,Et, C═CH₂, and cyclopropyl.

L can be a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene, —S—C₀₋₅alkylene, or—NH—C₀₋₅alkylene, and for C₂₋₆alkylene, —O—C₂₋₅alkylene, —S—C₂-alkylene,and NH—C₂₋₅alkylene, one carbon atom of the alkylene group canoptionally be replaced with O, S, or NH. For example, L can be —CH₂—NH—when a carbon on a C₂ alkylene group is replaced with NH, or—O—CH₂CH₂—O—, when a carbon on a O—C₃alkylene group is replaced with aO. Other options with substitution of C₃, C₄, C₅, or C₆ alkylene with O,S, or NH are specifically contemplated. In some embodiments, L isC₁₋₂alkylene, O, S, or NH. In some embodiments, L is a bond.

Ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring. Some specifically contemplated ringsinclude cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl,piperidinyl, azepanyl, imidazolidinyl, hexahydropyrimidinyl,hexahydropyridazinyl, tetrahydrofuranyl, tetrahydrothiofuranyl,azetidinyl, spiroheptyl, spirooctyl, spirononyl, spirodecyl,diazabicyclodecyl, diazabicyclononyl, diazabicyclooctyl,diazabicycloheptyl, hexahydropyrrolopyridyl, octahydropyrrolopyridyl,and octahydropyrrolopyrimidinyl. In various embodiments, ring A cancomprise piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In someembodiments, ring A comprises piperidinyl. Ring A can be furthersubstituted with one to three substituents. Some non-limiting examplesof substitutions on ring A include one to three substituents selectedfrom alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxylic acid or ester,haloalkyl, alkylamine, C(O)NH₂, oxo, halo, cyano, and isocyano.

When R⁴ is

ring A can be, for example,

More specifically, when R⁴ is

ring A can be, for example,

When R⁴ is

it can more specifically be

In such embodiments, ring A can be, for example,

R⁵ and R⁶ are substituents on the acrylamide moiety of the KRASinhibitors disclosed herein. In some embodiments, each of R⁵ and R⁶ isH. Some specifically contemplated R⁵ substituents include H, Br, Cl, F,CN, CH₃, CF₃, CH₂Br, CH₂OH, CH₂CH₂OH, CH₂OCH₂phenyl, cyclopropyl,phenyl, CH₂phenyl, CH₂OCH₃, CH₂N(CH₃)₂, CH₂N(CH₂CH₃)₂, CH₂CO₂H,CH₂CO₂CH₃, CH₂NHC(O)CH₃, CH₂C(O)NHCH₃, CH₂OC(O)CH₃, or

Some specifically contemplated R⁶ substituents include phenyl,cyclopropyl, CH₃, CF₃, CH₂CH₃, CH₂NH₂, CH(CH₃)NH₂, CH(CH₃)₂NH₂, CH₂C₁,CH₂Br, CH₂OCH₃, CH₂Ophenyl, CH₂OH, CO₂H, CO₂CH₂CH₃, CH₂CO₂H, CH₂CH₂NH₂,CH₂CH₂OH, CH₂CH₂N(CH₃)₂, CH₂NHCH₃, C(O)NHCH₃, C(O)N(CH₃)₂,CH₂C(O)NHphenyl, CH₂CHF₂, CH₂F, CHF₂, CH₂NHC(O)CH₃, CH₂NHCH₂CH₂OH,CH₂NHCH₂CO₂H, CH₂NH(CH₃)CH₂CO₂CH₃, CH₂NHCH₂CH₂OCH₃,CH₂NH(CH₃)CH₂CH₂OCH₃, CH₂NH(CH₃)CH₂C(O)N(CH₃)₂, CH₂NH(CH₃)CH₂C(O)NHCH₃,CH₂CH₂CCH, CH₂NMe₂, CH₂NH(CH₃)CH₂CH₂OH, CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃,CH₂NHCH₂CHF₂, CH₂NHCH₂CH₃,

R⁵ and R⁶, together with the atoms to which they are attached, can forma 4-6 membered ring, e.g., a 5- or 6-membered ring. Such rings includeR⁵ and R⁶ together being

In most embodiments, R⁷ is H. However, in some embodiments, R⁷ ismethyl. In other embodiments, R⁷ and R⁵ together are —CH₂— or —C(O)CH₂—.

Some specifically contemplated options for the moiety

include

Some specifically contemplated R⁴ substituents include

Some specifically contemplated R^(4′) substituents can include

In another embodiment, the present invention discloses compounds havinga structure selected from:

These compounds can be used as intermediates in the process of makingcompounds in the present application.These compounds can be in the form of a pharmaceutically acceptable saltand in a pharmaceutical formulation with a pharmaceutically acceptableexcipient.

The following examples are labeled using a classification system inwhich the first number refers to the method used to synthesize thecompound, the second number is an identifying number, and the thirdnumber, if present, refers to the compound's order of elution in achromatographic separation process. If third number is absent, thecompound is a single compound or mixture of isomers. The sequentialnumbering of the Examples is interrupted and certain Example numbers areintentionally omitted due to formatting considerations. The “-” denotesthat no changes were made, or no entries are in the relevant box.Specifically contemplated compounds include those as listed in Table 1:

TABLE 1 Ex. # Chemical Structure 1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-19-1

1-19-2

1-20

1-21

1-22

1-23

1-28

2-2

2-3

2-4

2-5

2-5-1

2-5-2

2-6

2-6-1

2-6-2

2-7

2-8

2-9

2-10

3-1

3-1-1

3-1-2

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

3-10

3-11

3-12

3-13

3-14

3-15

3-16

3-17

3-18

3-19

3-20

3-21

3-22

3-23

3-24

3-25

4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

5-1

5-2

5-3

5-4

5-5

5-6

5-7

5-8

5-9

6-1

6-2

7-1

7-2

7-3

8-1

8-1-1

8-1-2

8-2

8-3

8-3-1

8-3-2

8-4

8-5

8-6

8-6-1

8-6-2

9-1

9-2

9-3

9-4

9-5

9-6

9-7-1

9-7-2

9-9

9-10

9-11

9-12

9-13

9-14

10-1

10-2

10-3

10-4

10-5

10-6

10-7

10-8

10-9

10-10

10-11

10-12

10-13

11-1-1

11-1-2

11-2-2

12

13

14

15

16

17-1

17-2

18-1

18-2

18-3

19-1

19-2

19-3

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

NA NA 1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-19-1

1-19-2

1-20

1-21

1-22

1-23

1-28

2-1

2-2

2-3

2-4

2-5

2-5-1

2-5-2

2-6

2-6-1

2-6-2

3-1

3-1-1

3-1-2

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

3-10

3-11

3-12

3-13

3-14

3-15

3-16

3-17

3-18

3-19

3-20

3-21

3-22

3-23

3-24

3-25

4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

5-1

5-2

5-3

5-4

5-5

5-6

5-7

5-8

5-9

6-1

6-2

7-1

7-2

7-3

8-1

8-1-1

8-1-2

8-2

8-3

8-3-1

8-3-2

8-4

8-5

8-6

8-6-1

8-6-2

9-1

9-2

9-3

9-4

9-5

9-6

9-7-1

9-7-2

9-9

9-10

9-11

9-12

9-13

9-14

10-1

10-2

10-3

10-4

10-5

10-6

10-7

10-8

10-9

10-10

10-11

10-12

10-13

11-1-1

11-1-2

11-2-1

11-2-2

12

13

14

15

16

17-1

17-2

18-1

18-2

18-3

19-1

19-2

19-3

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

- - - - - -

Synthesis of Disclosed Compounds

Compounds as disclosed herein can be synthesized via a number ofspecific methods. The examples which outline specific synthetic routes,and the generic schemes below are meant to provide guidance to theordinarily skilled synthetic chemist, who will readily appreciate thatthe solvent, concentration, reagent, protecting group, order ofsynthetic steps, time, temperature, and the like can be modified asnecessary, well within the skill and judgment of the ordinarily skilledartisan.

Method 1

Method 1 synthesis: A compound of Formula (I) as disclosed herein can besynthesized as outlined in Method 1. An appropriate aromatic orheteroaromatic acid is reacted with a halogenating agent in Step 1 toform a halogenated aromatic or heteroaromatic acid. The acid is thenreacted with an amidating agent in Step 2 to form an amide intermediate.The amide intermediate is then reacted with a sulfurizing agent in Step3 to form a thioamide intermediate. Next, the thioamide intermediate isreacted with an oxidant in Step 4 to form the thiazole ring as shown.The amine of the thiazole is then converted to a leaving group in Step 5using an activating agent. The leaving group is then replaced with an R⁴protected group, as shown in Step 6. The R² moiety is then introduced inStep 7 by a cross-coupling reaction with the appropriate R² (protected)reagent with the X halide on the thiazole intermediate. Then, in Step 8,the R⁴ group is deprotected under appropriate conditions, depending uponthe protecting group used, the R⁴ group is then acylated to introducethe acrylamide moiety as shown, and lastly, R² is deprotected.Appropriate protecting groups and deprotection reagents are known tothose skilled in the art, e.g., as discussed in Greene's ProtectiveGroups in Organic Synthesis.

Contemplated halogenating agents include, but are not limited to,chlorine, bromine, N-chlorosuccinimide, and N-bromosuccinimide,optionally in the presence of a catalyst, e.g., iron or aluminum. Theordinarily skilled synthetic chemist will readily understand that otherhalogenating agents and catalysts can be used.

Contemplated amidating agents include, but are not limited to, N,N′-diisopropylcarbodiimide,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide,benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,thionyl chloride, isobutyl chloroformate, diethyl cyanophosphonate,carbonyl diimidazole, and polyphosphonic anhydride. The ordinarilyskilled synthetic chemist will readily understand that other amidatingagents can be used.

Contemplated sulfurizing agents include, but are not limited to, sulfur,phosphorus pentasulfide, and Lawesson's reagent. The ordinarily skilledsynthetic chemist will readily understand that other sulfurizing agentscan be used.

Contemplated oxidants include, but are not limited to, hydrogenperoxide, iodobenzene diacetate, t-butyl hydroperoxide,N-bromosuccinimide, and ammonium peroxodisulfate. The ordinarily skilledsynthetic chemist will readily understand that other oxidants can beused.

Contemplated activating agents include, but are not limited to, sodiumnitrite and t-butyl nitrite. The ordinarily skilled synthetic chemistwill readily understand that other activating agents can be used.

Contemplated cross-coupling reactions include, but are not limited to,Suzuki coupling, Negishi coupling, Hiyama coupling, Kumada coupling, andStille coupling. The ordinarily skilled chemist will readily understandthat couplings as shown in Method 1 can be performed under a number ofconditions.

Method 2

Method 2 synthesis: Method 2 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. Afterhalogenation in Step 1, the R⁴ protected group is introduced by reactionwith the acid in a coupling reaction in Step 2. The oxo group istransformed to a sulfur using a sulfurizing agent in Step 3. Then thethiazole ring is formed in the presence of an oxidant in Step 4. Theremaining steps 5-8 are analogous to steps 7 and 8 in Method 1 describedabove.

Method 3

Method 3 synthesis: Method 3 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. The R⁴ groupof the isothiazole intermediate is deprotected and acylated in Step 1 tointroduce the acrylamide moiety. The R² moiety is then introduced inStep 2 by a cross-coupling reaction with the appropriate R² (protected)reagent with the X halide on the isothiazole intermediate. Lastly, theR² group is deprotected in Step 3.

Method 4

Method 4 synthesis: Method 4 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. Aftersubstituting a leaving group on an isothiazole intermediate with aprotected R⁴ group, as depicted in Step 1, the R⁴ group intermediate isdeprotected and acylated in Step 2 to introduce the acrylamide moiety.The R² moiety is introduced by a cross-coupling reaction in Step 3, asin Method 1, and the R² group is deprotected in Step 4.

Method 5

Method 5 synthesis: Method 5 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. In thisalternative, the R² moiety is first introduced by a cross-coupling withthe X halide on the aromatic or heteroaromatic amide intermediate shownin Step 1. The amide intermediate is then reacted with a sulfurizingagent in Step 2 to form a thioamide intermediate. Oxidation of thisintermediate provides the isothiazole ring in Step 3. The amine group isthen converted to a leaving group in Step 4 and subsequently substitutedwith a protected R⁴ group in Step 5. Finally, in Step 6, the R⁴ group isdeprotected and reacted with an acylating agent, and then the R² groupis deprotected.

Method 6

Method 6 synthesis: Method 6 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. In thisalternative, an isothiazole intermediate is reacted with a metalatingagent to activate the X halide. The R² group is then introduced byreacting the activated intermediate with the appropriate R² (protected)reagent. In the last step, the R⁴ group is deprotected and acylated tointroduce the acrylamide moiety.

Contemplated metalating agents include, but are not limited to,bis(pinacolato)diboron, magnesium, zinc, hexamethyldistannane, andn-butyllithium. The ordinarily skilled synthetic chemist will readilyunderstand that other metalating agents and catalysts can be used.

Method 7

Method 7 synthesis: Method 7 provides an alternative method forformation of compounds of Formula (I) as disclosed herein. The R² moietyis first introduced by a cross-coupling with the X halide on thearomatic or heteroaromatic acid intermediate shown in Step 1. The acidmoiety is then reacted with the appropriate R⁴ (protected) reagent inthe presence of an amidating agent in Step 2. The carbonyl group of theacid derivative is then converted to a thiocarbonyl group in Step 3using a sulfurizing agent. The thioacid derivative is then reacted withan oxidant to form the isothiazole intermediate in Step 4. Lastly, theR⁴ group is deprotected and acylated to introduce the acrylamide moiety,and the R² group is deprotected.

Method 8

Method 8 synthesis: A compound of Formula (II) as disclosed herein canbe synthesized as outlined in Method 8. An appropriate aromatic orheteroaromatic acid is reacted with an amidating agent in Step 1 to forma primary amide intermediate. The amide is then reacted with anisocyanate-forming reagent and a R¹⁰-substituted amine to form a ureaintermediate. Contemplated isocyanate-forming agents include oxalylchloride, thionyl chloride, and phosphorus oxychloride. The ureaintermediate is then reacted with a cyclization agent in Step 3 to formthe quinazolinedione ring shown. Contemplated cyclization agentsinclude, but are not limited to, bases such as potassiumhexamethyldisilazide, potassium tert-butoxide, sodium hydride, andphosphazene bases. The R² moiety is then introduced in Step 4 by across-coupling reaction with the appropriate R² (protected) reagent withthe X halide on the quinazolinedione intermediate. An oxo group of thequinazolinedione is then converted to a leaving group in Step 5 using anactivating agent. Contemplated activating agents include, but are notlimited to, thionyl chloride, triflic anhydride, phosphorus oxychloride,and phosphorus pentachloride. The leaving group is then replaced with anR⁴ protected group to form a substituted quinazolinone, as shown in Step6. The remaining deprotection-acylation-deprotection sequence shown inSteps 7-9 are analogous to Step 8 in Method 1.

Method 9

Method 9 synthesis: Method 9 provides an alternative method forformation of compounds of Formula (II) as disclosed herein. An oxo groupof the quinazolinedione is converted to a leaving group in Step 1. Step2 involves the introduction of the R⁴ (protected) group, deprotection ofthe R⁴ group, and acylation of the free R⁴ group. The R² group isintroduced in Step 3 by a cross-coupling reaction with the appropriateR² (protected) reagent with the X halide on the quinazolinedioneintermediate. Finally, the R² group is deprotected.

Method 10

Method 10 synthesis: A compound of Formula (V) as disclosed herein canbe synthesized as outlined in Method 10. The appropriate anhydride isreacted with hydrazine to form the phthalazinedione ring as shown inStep 1. The R² moiety is introduced in Step 2 by a cross-couplingreaction with the appropriate R² reagent with the X halide on thequinazolinedione intermediate. The R² group is then protected in Step 3.The phthalazinedione ring is halogenated twice. Contemplatedhalogenating agent include thionyl chloride, phosphorus oxychloride, andoxalyl chloride. One of the halogen groups is then replaced with an R⁴protected group to form a substituted phthalazine ring, as shown in Step5. Then, in Steps 6 and 7, the R⁴ group is deprotected under appropriateconditions, depending upon the protecting group used, and the free R⁴group is then acylated to introduce the acrylamide moiety. The R² isdeprotected in Step 8. Lastly, the R¹⁰ moiety is introduced in Step 9 bya cross-coupling reaction with the appropriate R¹⁰ reagent with the Xhalide on the phthalazine intermediate.

Method 11

Method 11 synthesis: Method 11 provides an alternative method forformation of compounds of Formula (II) as disclosed herein. An oxo groupof the quinazolinedione is converted to a leaving group in Step 1. TheR⁴ (protected) group is introduced in Step 2. The R² group is introducedin Step 3 by a cross-coupling reaction with the appropriate R²(protected) reagent with the X halide on the quinazolinedioneintermediate. Lastly, the R⁴ group is deprotected and subsequentlyacylated in Steps 4 and 5.

Pharmaceutical Compositions, Dosing, and Routes of Administration

Also provided herein are pharmaceutical compositions that includes acompound as disclosed herein, together with a pharmaceuticallyacceptable excipient, such as, for example, a diluent or carrier.Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the compound can be administeredin an effective amount to achieve its intended purpose. Administrationof the compound described in more detail below.

Suitable pharmaceutical formulations can be determined by the skilledartisan depending on the route of administration and the desired dosage.See, e.g., Remington's Pharmaceutical Sciences, 1435-712 (18th ed., MackPublishing Co, Easton, Pa., 1990). Formulations may influence thephysical state, stability, rate of in vivo release and rate of in vivoclearance of the administered agents. Depending on the route ofadministration, a suitable dose may be calculated according to bodyweight, body surface areas or organ size. Further refinement of thecalculations necessary to determine the appropriate treatment dose isroutinely made by those of ordinary skill in the art without undueexperimentation, especially in light of the dosage information andassays disclosed herein as well as the pharmacokinetic data obtainablethrough animal or human clinical trials.

The phrases “pharmaceutically acceptable” or “pharmacologicallyacceptable” refer to molecular entities and compositions that do notproduce adverse, allergic, or other untoward reactions when administeredto an animal or a human. As used herein, “pharmaceutically acceptableexcipients” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such excipients for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the therapeuticcompositions, its use in therapeutic compositions is contemplated.Supplementary active ingredients also can be incorporated into thecompositions. In exemplary embodiments, the formulation may comprisecorn syrup solids, high-oleic safflower oil, coconut oil, soy oil,L-leucine, calcium phosphate tribasic, L-tyrosine, L-proline, L-lysineacetate, DATEM (an emulsifier), L-glutamine, L-valine, potassiumphosphate dibasic, L-isoleucine, L-arginine, L-alanine, glycine,L-asparagine monohydrate, L-serine, potassium citrate, L-threonine,sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbicacid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride,L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol,ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-camitine,alpha-tocopheryl acetate, sodium chloride, niacinamide, mixedtocopherols, calcium pantothenate, cupric sulfate, thiamine chloridehydrochloride, vitamin A palmitate, manganese sulfate, riboflavin,pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide,phylloquinone, biotin, sodium selenate, chromium chloride, sodiummolybdate, vitamin D3 and cyanocobalamin.

The compound can be present in a pharmaceutical composition as apharmaceutically acceptable salt. As used herein, “pharmaceuticallyacceptable salts” include, for example base addition salts and acidaddition salts.

Pharmaceutically acceptable base addition salts may be formed withmetals or amines, such as alkali and alkaline earth metals or organicamines. Pharmaceutically acceptable salts of compounds may also beprepared with a pharmaceutically acceptable cation. Suitablepharmaceutically acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations. Carbonates or hydrogen carbonates are also possible.Examples of metals used as cations are sodium, potassium, magnesium,ammonium, calcium, or ferric, and the like. Examples of suitable aminesinclude isopropylamine, trimethylamine, histidine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts include inorganic ororganic acid salts. Examples of suitable acid salts include thehydrochlorides, formates, acetates, citrates, salicylates, nitrates,phosphates. Other suitable pharmaceutically acceptable salts are wellknown to those skilled in the art and include, for example, formic,acetic, citric, oxalic, tartaric, or mandelic acids, hydrochloric acid,hydrobromic acid, sulfuric acid or phosphoric acid; with organiccarboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamicacids, for example acetic acid, trifluoroacetic acid (TFA), propionicacid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid,oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, salicylic acid,4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid,embonic acid, nicotinic acid or isonicotinic acid; and with amino acids,such as the 20 alpha amino acids involved in the synthesis of proteinsin nature, for example glutamic acid or aspartic acid, and also withphenylacetic acid, methanesulfonic acid, ethanesulfonic acid,2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid,benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulfamic acid (withthe formation of cyclamates), or with other acid organic compounds, suchas ascorbic acid.

Pharmaceutical compositions containing the compounds disclosed hereincan be manufactured in a conventional manner, e.g., by conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Proper formulationis dependent upon the route of administration chosen.

For oral administration, suitable compositions can be formulated readilyby combining a compound disclosed herein with pharmaceuticallyacceptable excipients such as carriers well known in the art. Suchexcipients and carriers enable the present compounds to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a patient to be treated.Pharmaceutical preparations for oral use can be obtained by adding acompound as disclosed herein with a solid excipient, optionally grindinga resulting mixture, and processing the mixture of granules, afteradding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients include, for example, fillers and cellulosepreparations. If desired, disintegrating agents can be added.Pharmaceutically acceptable ingredients are well known for the varioustypes of formulation and may be for example binders (e.g., natural orsynthetic polymers), lubricants, surfactants, sweetening and flavoringagents, coating materials, preservatives, dyes, thickeners, adjuvants,antimicrobial agents, antioxidants and carriers for the variousformulation types.

When a therapeutically effective amount of a compound disclosed hereinis administered orally, the composition typically is in the form of asolid (e.g., tablet, capsule, pill, powder, or troche) or a liquidformulation (e.g., aqueous suspension, solution, elixir, or syrup).

When administered in tablet form, the composition can additionallycontain a functional solid and/or solid carrier, such as a gelatin or anadjuvant. The tablet, capsule, and powder can contain about 1 to about95% compound, and preferably from about 15 to about 90% compound.

When administered in liquid or suspension form, a functional liquidand/or a liquid carrier such as water, petroleum, or oils of animal orplant origin can be added. The liquid form of the composition canfurther contain physiological saline solution, sugar alcohol solutions,dextrose or other saccharide solutions, or glycols. When administered inliquid or suspension form, the composition can contain about 0.5 toabout 90% by weight of a compound disclosed herein, and preferably about1 to about 50% of a compound disclosed herein. In one embodimentcontemplated, the liquid carrier is non-aqueous or substantiallynon-aqueous. For administration in liquid form, the composition may besupplied as a rapidly-dissolving solid formulation for dissolution orsuspension immediately prior to administration.

When a therapeutically effective amount of a compound disclosed hereinis administered by intravenous, cutaneous, or subcutaneous injection,the composition is in the form of a pyrogen-free, parenterallyacceptable aqueous solution. The preparation of such parenterallyacceptable solutions, having due regard to pH, isotonicity, stability,and the like, is within the skill in the art. A preferred compositionfor intravenous, cutaneous, or subcutaneous injection typicallycontains, in addition to a compound disclosed herein, an isotonicvehicle. Such compositions may be prepared for administration assolutions of free base or pharmacologically acceptable salts in watersuitably mixed with a surfactant, such as hydroxypropylcellulose.Dispersions also can be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof and in oils. Under ordinary conditions ofstorage and use, these preparations can optionally contain apreservative to prevent the growth of microorganisms.

Injectable compositions can include sterile aqueous solutions,suspensions, or dispersions and sterile powders for the extemporaneouspreparation of sterile injectable solutions, suspensions, ordispersions. In all embodiments the form must be sterile and must befluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must resist thecontaminating action of microorganisms, such as bacteria and fungi, byoptional inclusion of a preservative. The carrier can be a solvent ordispersion medium containing, for example, water, ethanol, polyol (e.g.,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. In one embodimentcontemplated, the carrier is non-aqueous or substantially non-aqueous.The proper fluidity can be maintained, for example, by the use of acoating, such as lecithin, by the maintenance of the required particlesize of the compound in the embodiment of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many embodiments, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the embodiment ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Slow release or sustained release formulations may also be prepared inorder to achieve a controlled release of the active compound in contactwith the body fluids in the GI tract, and to provide a substantiallyconstant and effective level of the active compound in the blood plasma.For example, release can be controlled by one or more of dissolution,diffusion, and ion-exchange. In addition, the slow release approach mayenhance absorption via saturable or limiting pathways within the GItract. For example, the compound may be embedded for this purpose in apolymer matrix of a biological degradable polymer, a water-solublepolymer or a mixture of both, and optionally suitable surfactants.Embedding can mean in this context the incorporation of micro-particlesin a matrix of polymers. Controlled release formulations are alsoobtained through encapsulation of dispersed micro-particles oremulsified micro-droplets via known dispersion or emulsion coatingtechnologies.

For administration by inhalation, compounds of the present invention areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant.In the embodiment of a pressurized aerosol, the dosage unit can bedetermined by providing a valve to deliver a metered amount. Capsulesand cartridges of, e.g., gelatin, for use in an inhaler or insufflatorcan be formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

The compounds disclosed herein can be formulated for parenteraladministration by injection (e.g., by bolus injection or continuousinfusion). Formulations for injection can be presented in unit dosageform (e.g., in ampules or in multidose containers), with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the compounds in water-soluble form. Additionally,suspensions of the compounds can be prepared as appropriate oilyinjection suspensions. Suitable lipophilic solvents or vehicles includefatty oils or synthetic fatty acid esters. Aqueous injection suspensionscan contain substances which increase the viscosity of the suspension.Optionally, the suspension also can contain suitable stabilizers oragents that increase the solubility of the compounds and allow for thepreparation of highly concentrated solutions. Alternatively, a presentcomposition can be in powder form for constitution with a suitablevehicle (e.g., sterile pyrogen-free water) before use.

Compounds disclosed herein also can be formulated in rectalcompositions, such as suppositories or retention enemas (e.g.,containing conventional suppository bases). In addition to theformulations described previously, the compounds also can be formulatedas a depot preparation. Such long-acting formulations can beadministered by implantation (e.g., subcutaneously or intramuscularly)or by intramuscular injection. Thus, for example, the compounds can beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

In particular, a compound disclosed herein can be administered orally,buccally, or sublingually in the form of tablets containing excipients,such as starch or lactose, or in capsules or ovules, either alone or inadmixture with excipients, or in the form of elixirs or suspensionscontaining flavoring or coloring agents. Such liquid preparations can beprepared with pharmaceutically acceptable additives, such as suspendingagents. A compound also can be injected parenterally, for example,intravenously, intramuscularly, subcutaneously, or intracoronarily. Forparenteral administration, the compound is best used in the form of asterile aqueous solution which can contain other substances, forexample, salts, or sugar alcohols, such as mannitol, or glucose, to makethe solution isotonic with blood.

For veterinary use, a compound disclosed herein is administered as asuitably acceptable formulation in accordance with normal veterinarypractice. The veterinarian can readily determine the dosing regimen androute of administration that is most appropriate for a particularanimal.

In some embodiments, all the necessary components for the treatment ofKRAS-related disorder using a compound as disclosed herein either aloneor in combination with another agent or intervention traditionally usedfor the treatment of such disease may be packaged into a kit.Specifically, the present invention provides a kit for use in thetherapeutic intervention of the disease comprising a packaged set ofmedicaments that include the compound disclosed herein as well asbuffers and other components for preparing deliverable forms of saidmedicaments, and/or devices for delivering such medicaments, and/or anyagents that are used in combination therapy with the compound disclosedherein, and/or instructions for the treatment of the disease packagedwith the medicaments. The instructions may be fixed in any tangiblemedium, such as printed paper, or a computer readable magnetic oroptical medium, or instructions to reference a remote computer datasource such as a world wide web page accessible via the internet.

A “therapeutically effective amount” means an amount effective to treator to prevent development of, or to alleviate the existing symptoms of,the subject being treated. Determination of the effective amounts iswell within the capability of those skilled in the art, especially inlight of the detailed disclosure provided herein. Generally, a“therapeutically effective dose” refers to that amount of the compoundthat results in achieving the desired effect. For example, in onepreferred embodiment, a therapeutically effective amount of a compounddisclosed herein decreases KRAS activity by at least 5%, compared tocontrol, at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, or at least 90%.

The amount of compound administered can be dependent on the subjectbeing treated, on the subject's age, health, sex, and weight, the kindof concurrent treatment (if any), severity of the affliction, the natureof the effect desired, the manner and frequency of treatment, and thejudgment of the prescribing physician. The frequency of dosing also canbe dependent on pharmacodynamic effects on arterial oxygen pressures.However, the most preferred dosage can be tailored to the individualsubject, as is understood and determinable by one of skill in the art,without undue experimentation. This typically involves adjustment of astandard dose (e.g., reduction of the dose if the patient has a low bodyweight).

While individual needs vary, determination of optimal ranges ofeffective amounts of the compound is within the skill of the art. Foradministration to a human in the curative or prophylactic treatment ofthe conditions and disorders identified herein, for example, typicaldosages of the compounds of the present invention can be about 0.05mg/kg/day to about 50 mg/kg/day, for example at least 0.05 mg/kg, atleast 0.08 mg/kg, at least 0.1 mg/kg, at least 0.2 mg/kg, at least 0.3mg/kg, at least 0.4 mg/kg, or at least 0.5 mg/kg, and preferably 50mg/kg or less, 40 mg/kg or less, 30 mg/kg or less, 20 mg/kg or less, or10 mg/kg or less, which can be about 2.5 mg/day (0.5 mg/kg×5 kg) toabout 5000 mg/day (50 mg/kg×100 kg), for example. For example, dosagesof the compounds can be about 0.1 mg/kg/day to about 50 mg/kg/day, about0.05 mg/kg/day to about 10 mg/kg/day, about 0.05 mg/kg/day to about 5mg/kg/day, about 0.05 mg/kg/day to about 3 mg/kg/day, about 0.07mg/kg/day to about 3 mg/kg/day, about 0.09 mg/kg/day to about 3mg/kg/day, about 0.05 mg/kg/day to about 0.1 mg/kg/day, about 0.1mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 10 mg/kg/day,about 1 mg/kg/day to about 5 mg/kg/day, about 1 mg/kg/day to about 3mg/kg/day, about 3 mg/day to about 500 mg/day, about 5 mg/day to about250 mg/day, about 10 mg/day to about 100 mg/day, about 3 mg/day to about10 mg/day, or about 100 mg/day to about 250 mg/day. Such doses may beadministered in a single dose or it may be divided into multiple doses.

Methods of Using KRAS G12C Inhibitors

The present disclosure provides a method of inhibiting RAS-mediated cellsignaling comprising contacting a cell with an effective amount of oneor more compounds disclosed herein. Inhibition of RAS-mediated signaltransduction can be assessed and demonstrated by a wide variety of waysknown in the art. Non-limiting examples include a showing of (a) adecrease in GTPase activity of RAS; (b) a decrease in GTP bindingaffinity or an increase in GDP binding affinity; (c) an increase in Koff of GTP or a decrease in K off of GDP; (d) a decrease in the levelsof signaling transduction molecules downstream in the RAS pathway, suchas a decrease in pMEK, pERK, or pAKT levels; and/or (e) a decrease inbinding of RAS complex to downstream signaling molecules including butnot limited to Raf. Kits and commercially available assays can beutilized for determining one or more of the above.

The disclosure also provides methods of using the compounds orpharmaceutical compositions of the present disclosure to treat diseaseconditions, including but not limited to conditions implicated by G12CKRAS, HRAS or NRAS mutation (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound as disclosedherein to a subject in need thereof. In some embodiments, the cancer ismediated by a KRAS, HRAS or NRAS G12C mutation. In various embodiments,the cancer is pancreatic cancer, colorectal cancer or lung cancer. Insome embodiments, the cancer is gall bladder cancer, thyroid cancer, andbile duct cancer.

In some embodiments the disclosure provides method of treating adisorder in a subject in need thereof, wherein the said method comprisesdetermining if the subject has a KRAS, HRAS or NRAS G12C mutation and ifthe subject is determined to have the KRAS, HRAS or NRAS G12C mutation,then administering to the subject a therapeutically effective dose of atleast one compound as disclosed herein or a pharmaceutically acceptablesalt thereof.

The disclosed compounds inhibit anchorage-independent cell growth andtherefore have the potential to inhibit tumor metastasis. Accordingly,another embodiment the disclosure provides a method for inhibiting tumormetastasis, the method comprising administering an effective amount acompound disclosed herein.

KRAS, HRAS or NRAS G12C mutations have also been identified inhematological malignancies (e.g., cancers that affect blood, bone marrowand/or lymph nodes). Accordingly, certain embodiments are directed toadministration of a disclosed compounds (e.g., in the form of apharmaceutical composition) to a patient in need of treatment of ahematological malignancy. Such malignancies include, but are not limitedto leukemias and lymphomas. For example, the presently disclosedcompounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/or otherleukemias. In other embodiments, the compounds are useful for treatmentof lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkinslymphoma. In various embodiments, the compounds are useful for treatmentof plasma cell malignancies such as multiple myeloma, mantle celllymphoma, and Waldenstrom's macroglubunemia.

Determining whether a tumor or cancer comprises a G12C KRAS, HRAS orNRAS mutation can be undertaken by assessing the nucleotide sequenceencoding the KRAS, HRAS or NRAS protein, by assessing the amino acidsequence of the KRAS, HRAS or NRAS protein, or by assessing thecharacteristics of a putative KRAS, HRAS or NRAS mutant protein. Thesequence of wild-type human KRAS, HRAS or NRAS is known in the art,(e.g. Accession No. NP203524).

Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotidesequence are known by those of skill in the art. These methods include,but are not limited to, polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) assays, polymerase chain reaction-singlestrand conformation polymorphism (PCR-SSCP) assays, real-time PCRassays, PCR sequencing, mutant allele-specific PCR amplification (MASA)assays, direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, samples are evaluated for G12C KRAS, HRASor NRAS mutations by real-time PCR. In real-time PCR, fluorescent probesspecific for the KRAS, HRAS or NRAS G12C mutation are used. When amutation is present, the probe binds and fluorescence is detected. Insome embodiments, the KRAS, HRAS or NRAS G12C mutation is identifiedusing a direct sequencing method of specific regions (e.g., exon 2and/or exon 3) in the KRAS, HRAS or NRAS gene. This technique willidentify all possible mutations in the region sequenced.

Methods for detecting a mutation in a KRAS, HRAS or NRAS protein areknown by those of skill in the art. These methods include, but are notlimited to, detection of a KRAS, HRAS or NRAS mutant using a bindingagent (e.g., an antibody) specific for the mutant protein, proteinelectrophoresis and Western blotting, and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a G12C KRAS,HRAS or NRAS mutation can use a variety of samples. In some embodiments,the sample is taken from a subject having a tumor or cancer. In someembodiments, the sample is a fresh tumor/cancer sample. In someembodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is a circulating tumor cell (CTC) sample.In some embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

The disclosure also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound as disclosed herein, or apharmaceutically acceptable salt thereof. In some embodiments, saidmethod relates to the treatment of a subject who suffers from a cancersuch as acute myeloid leukemia, cancer in adolescents, adrenocorticalcarcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi'sSarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, or viral-induced cancer. In some embodiments, said methodrelates to the treatment of a non-cancerous hyperproliferative disordersuch as benign hyperplasia of the skin (e. g., psoriasis), restenosis,or prostate (e. g., benign prostatic hypertrophy (BPH)).

In some embodiments, the methods for treatment are directed to treatinglung cancers, the methods comprise administering an effective amount ofany of the above described compound (or a pharmaceutical compositioncomprising the same) to a subject in need thereof. In certainembodiments the lung cancer is a non-small cell lung carcinoma (NSCLC),for example adenocarcinoma, squamous-cell lung carcinoma or large-celllung carcinoma. In some embodiments, the lung cancer is a small celllung carcinoma. Other lung cancers treatable with the disclosedcompounds include, but are not limited to, glandular tumors, carcinoidtumors and undifferentiated carcinomas.

The disclosure further provides methods of modulating a G12C MutantKRAS, HRAS or NRAS protein activity by contacting the protein with aneffective amount of a compound of the disclosure. Modulation can beinhibiting or activating protein activity. In some embodiments, thedisclosure provides methods of inhibiting protein activity by contactingthe G12C Mutant KRAS, HRAS or NRAS protein with an effective amount of acompound of the disclosure in solution. In some embodiments, thedisclosure provides methods of inhibiting the G12C Mutant KRAS, HRAS orNRAS protein activity by contacting a cell, tissue, or organ thatexpresses the protein of interest. In some embodiments, the disclosureprovides methods of inhibiting protein activity in subject including butnot limited to rodents and mammal (e.g., human) by administering intothe subject an effective amount of a compound of the disclosure. In someembodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%,70%, 80%, or 90%. In some embodiments, the percentage of inhibitingexceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the disclosure provides methods of inhibiting KRAS,HRAS or NRAS G12C activity in a cell by contacting said cell with anamount of a compound of the disclosure sufficient to inhibit theactivity of KRAS, HRAS or NRAS G12C in said cell. In some embodiments,the disclosure provides methods of inhibiting KRAS, HRAS or NRAS G12Cactivity in a tissue by contacting said tissue with an amount of acompound of the disclosure sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said tissue. In some embodiments, the disclosureprovides methods of inhibiting KRAS, HRAS or NRAS G12C activity in anorganism by contacting said organism with an amount of a compound of thedisclosure sufficient to inhibit the activity of KRAS, HRAS or NRAS G12Cin said organism. In some embodiments, the disclosure provides methodsof inhibiting KRAS, HRAS or NRAS G12C activity in an animal bycontacting said animal with an amount of a compound of the disclosuresufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in saidanimal. In some embodiments, the disclosure provides methods ofinhibiting KRAS, HRAS or NRAS G12C activity in a mammal by contactingsaid mammal with an amount of a compound of the disclosure sufficient toinhibit the activity of KRAS, HRAS or NRAS G12C in said mammal. In someembodiments, the disclosure provides methods of inhibiting KRAS, HRAS orNRAS G12C activity in a human by contacting said human with an amount ofa compound of the disclosure sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said human. The present disclosure provides methodsof treating a disease mediated by KRAS, HRAS or NRAS G12C activity in asubject in need of such treatment.

Combination Therapy:

The present disclosure also provides methods for combination therapiesin which an agent known to modulate other pathways, or other componentsof the same pathway, or even overlapping sets of target enzymes are usedin combination with a compound of the present disclosure, or apharmaceutically acceptable salt thereof. In one aspect, such therapyincludes but is not limited to the combination of one or more compoundsof the disclosure with chemotherapeutic agents, therapeutic antibodies,and radiation treatment, to provide a synergistic or additivetherapeutic effect.

Many chemotherapeutics are presently known in the art and can be used incombination with the compounds of the disclosure. In some embodiments,the chemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Kyprolis® (carfilzomib),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlomaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel and docetaxel; retinoic acid; esperamicins; capecitabine; andpharmaceutically acceptable salts, acids or derivatives of any of theabove.

Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen,(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylomithine (DMFO).

Where desired, the compounds or pharmaceutical composition of thepresent disclosure can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

This disclosure further relates to a method for using the compounds orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the disclosure in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present disclosure include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions of the disclosure can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the disclosure and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include alecoxib,valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 WO 96/27583 European PatentPublication EP0818442, European Patent Publication EP1004578, WO98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO98/30566, European Patent Publication 606046, European PatentPublication 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667,WO 99/007675, European Patent Publication EP1786785, European PatentPublication No. EP1181017, United States Publication US20090012085,United States Publication U.S. Pat. No. 5,863,949, United StatesPublication U.S. Pat. No. 5,861,510, and European Patent PublicationEP0780386, all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or AMP-9 relative to the othermatrix-metalloproteinases (i. e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specificexamples of MMP inhibitors useful in the disclosure are AG-3340, RO32-3555, and RS 13-0830.

The present compounds may also be used in co-therapies with otheranti-neoplastic agents, such as acemannan, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid,amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim,ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide,broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine,clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab,denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel,docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine,carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa,daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab,eflomithine, emitefur, epirubicin, epoetin beta, etoposide phosphate,exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabinephosphate, formestane, fotemustine, gallium nitrate, gemcitabine,gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine,goserelin, heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-_(n3),interferon alfacon-1, interferon alpha, natural, interferon beta,interferon beta-1a, interferon beta-1b, interferon gamma, naturalinterferon gamma-1a, interferon gamma-1b, interleukin-1 beta,iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult),leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alphainterferon, leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin,lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide,mifepristone, miltefosine, mirimostim, mismatched double stranded RNA,mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,naloxone+pentazocine, nartograstim, nedaplatin, nilutamide, noscapine,novel erythropoiesis stimulating protein, NSC 631570 octreotide,oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid,pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate,RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aetema), ambamustine, antisense oligonucleotide, bcl-2(Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

The compounds of the invention may further be used with VEGFRinhibitors. Other compounds described in the following patents andpatent applications can be used in combination therapy: U.S. Pat. No.6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat. No. 6,235,764, WO01/32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat.No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S.Pat. No. 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO 04/05279,WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO 99/45009, WO00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO 00/12089, and WO00/02871.

In some embodiments, the combination comprises a composition of thepresent invention in combination with at least one anti-angiogenicagent. Agents are inclusive of, but not limited to, in vitrosynthetically prepared chemical compositions, antibodies, antigenbinding regions, radionuclides, and combinations and conjugates thereof.An agent can be an agonist, antagonist, allosteric modulator, toxin or,more generally, may act to inhibit or stimulate its target (e.g.,receptor or enzyme activation or inhibition), and thereby promote celldeath or arrest cell growth.

Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR(kinase domain receptor) inhibitory agents (e.g., antibodies and antigenbinding regions that specifically bind to the kinase domain receptor),anti-VEGF agents (e.g., antibodies or antigen binding regions thatspecifically bind VEGF, or soluble VEGF receptors or a ligand bindingregion thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptoragents (e.g., antibodies or antigen binding regions that specificallybind thereto), EGFR inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto) such as Vectibix(panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 andanti-Ang2 agents (e.g., antibodies or antigen binding regionsspecifically binding thereto or to their receptors, e.g., Tie2/Tek), andanti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen bindingregions that specifically bind thereto). The pharmaceutical compositionsof the present invention can also include one or more agents (e.g.,antibodies, antigen binding regions, or soluble receptors) thatspecifically bind and inhibit the activity of growth factors, such asantagonists of hepatocyte growth factor (HGF, also known as ScatterFactor), and antibodies or antigen binding regions that specificallybind its receptor “c-met”.

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tekantagonists (Ceretti et al., U.S. Publication No. 2003/0162712; U.S.Pat. No. 6,413,932), anti-TWEAK agents (e.g., specifically bindingantibodies or antigen binding regions, or soluble TWEAK receptorantagonists; see, Wiley, U.S. Pat. No. 6,727,225), ADAM disintegrindomain to antagonize the binding of integrin to its ligands (Fanslow etal., U.S. Publication No. 2002/0042368), specifically binding anti-ephreceptor and/or anti-ephrin antibodies or antigen binding regions (U.S.Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447;6,057,124 and patent family members thereof), and anti-PDGF-BBantagonists (e.g., specifically binding antibodies or antigen bindingregions) as well as antibodies or antigen binding regions specificallybinding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g.,antibodies or antigen binding regions that specifically bind thereto).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer,USA); cilengitide. (Merck KGaA, Germany, EPO 770622); pegaptaniboctasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA,(Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat, (Arriva, USA, U.S.Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783);vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA);TLC ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab,(Crucell, Netherlands) DAC: antiangiogenic, (ConjuChem, Canada);Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan);SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070);ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson,USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor,(Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236,(Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA);angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan);2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00,(IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan);TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelialgrowth factor antagonist, (Borean, Denmark); bevacizumab (pINN),(Genentech, USA); angiogenesis inhibitors, (SUGEN, USA); XL 784,(Exelixis, USA); XL 647, (Exelixis, USA); MAb, alpha5beta3 integrin,second generation, (Applied Molecular Evolution, USA and MedImmune,USA); gene therapy, retinopathy, (Oxford BioMedica, UK); enzastaurinhydrochloride (USAN), (Lilly, USA); CEP 7055, (Cephalon, USA andSanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer Research,Italy); angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist,(Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic, (XOMA, USA);PI 88, (Progen, Australia); cilengitide (pINN), (Merck KGaA, German;Munich Technical University, Germany, Scripps Clinic and ResearchFoundation, USA); cetuximab (INN), (Aventis, France); AVE 8062,(Ajinomoto, Japan); AS 1404, (Cancer Research Laboratory, New Zealand);SG 292, (Telios, USA); Endostatin, (Boston Childrens Hospital, USA); ATN161, (Attenuon, USA); ANGIOSTATIN, (Boston Childrens Hospital, USA);2-methoxyestradiol, (Boston Childrens Hospital, USA); ZD 6474,(AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458,(Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca,UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany);tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn),(Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea);vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation,USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California atSan Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA);troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503,(OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA);motuporamine C, (British Columbia University, Canada); CDP 791,(Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820,(Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna,Canada); vaccine, angiogenesis, (EntreMed, USA); urokinase plasminogenactivator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte,USA); HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAYRES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom,USA); KR 31372, (Korea Research Institute of Chemical Technology, SouthKorea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA);786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drugdelivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA);anginex, (Maastricht University, Netherlands, and Minnesota University,USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,(ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (NationalInstitute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (BostonChildrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems,USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor,(Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (SouthFlorida University, USA and Yale University, USA); CS 706, (Sankyo,Japan); combretastatin A4 prodrug, (Arizona State University, USA);chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925,(Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA); GCS100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD 732,(Chong Kun Dang, South Korea); MAb, vascular endothelium growth factor,(Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG 13577,(Aventis, France); WX 360, (Wilex, Germany); squalamine (plNN),(Genaera, USA); RPI 4610, (Sima, USA); cancer therapy, (Marinova,Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon,South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG,Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis,Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102,(Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA);VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin, (NationalInstitutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, Japan); TumStatin, (Beth Israel Hospital, USA); truncatedsoluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck &Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

Additional pharmaceutically active compounds/agents that can be used inthe treatment of cancers and that can be used in combination with one ormore compound of the present invention include: epoetin alfa;darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim;denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG951; and AMG 706, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a composition provided herein is conjointlyadministered with a chemotherapeutic agent. Suitable chemotherapeuticagents may include, natural products such as vinca alkaloids (e.g.,vinblastine, vincristine, and vinorelbine), paclitaxel,epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics(e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin), mitomycin, enzymes (e.g., L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine), antiplateletagents, antiproliferative/antimitotic alkylating agents such as nitrogenmustards (e.g., mechlorethamine, cyclophosphamide and analogs,melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g.,hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib,UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638,and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine(DTIC), antiproliferative/antimitotic antimetabolites such as folic acidanalogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxuridine, and cytarabine), purine analogs and related inhibitors(e.g., mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole,exemestane, and letrozole), and platinum coordination complexes (e.g.,cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g.,trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamicacid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTorinhibitors (e.g., temsirolimus, everolimus, ridaforolimus, andsirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents(e.g., Zalypsis), PI3K delta inhibitor (e.g., GS-1101 and TGR-1202),PI3K delta and gamma inhibitor (e.g., CAL-130), multi-kinase inhibitor(e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormoneagonists such as leutinizing hormone releasing hormone (LHRH) agonists(e.g., goserelin, leuprolide and triptorelin), BAFF-neutralizingantibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors,anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L),aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonalantibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab),HSP90 inhibitors (e.g., 17 AAG and KOS 953), PI3K/Akt inhibitors (e.g.,perifosine), Akt inhibitor (e.g., GSK-2141795), PKC inhibitors (e.g.,enzastaurin), FTIs (e.g., Zamestra™), anti-CD138 (e.g., BT062), Torc1/2specific kinase inhibitor (e.g., INK128), kinase inhibitor (e.g.,GS-1101), ER/UPR targeting agent (e.g., MKC-3946), cFMS inhibitor (e.g.,ARRY-382), JAK1/2 inhibitor (e.g., CYT387), PARP inhibitor (e.g.,olaparib and veliparib (ABT-888)), BCL-2 antagonist. Otherchemotherapeutic agents may include mechlorethamine, camptothecin,ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, orany analog or derivative variant of the foregoing.

The compounds of the present invention may also be used in combinationwith radiation therapy, hormone therapy, surgery and immunotherapy,which therapies are well known to those skilled in the art.

In certain embodiments, a pharmaceutical composition provided herein isconjointly administered with a steroid. Suitable steroids may include,but are not limited to, 21-acetoxypregnenolone, alclometasone,algestone, amcinonide, beclomethasone, betamethasone, budesonide,chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone,fluazacort, flucloronide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, hydrocortisone,loteprednol etabonate, mazipredone, medrysone, meprednisone,methylprednisolone, mometasone furoate, paramethasone, prednicarbate,prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodiumphosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and salts and/or derivatives thereof. In aparticular embodiment, the compounds of the present invention can alsobe used in combination with additional pharmaceutically active agentsthat treat nausea. Examples of agents that can be used to treat nauseainclude: dronabinol; granisetron; metoclopramide; ondansetron; andprochlorperazine; or a pharmaceutically acceptable salt thereof.

The compounds or pharmaceutical compositions of the disclosure can alsobe used in combination with an amount of one or more substances selectedfrom EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors,TOR inhibitors, and immune therapies, including anti-PD-1, anti-PDL-1,anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells,and BiTEs.

EGFR inhibitors include, but are not limited to, small moleculeantagonists, antibody inhibitors, or specific antisense nucleotide orsiRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux),panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Smallmolecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), andmost recently, lapatinib (TykerB). See e.g., Yan L, et. al.,Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic AntibodyDevelopment, BioTechniques 2005; 39(4): 565-8, and Paez J G, et. al.,EGFR Mutations In Lung Cancer Correlation With Clinical Response ToGefitinib Therapy, Science 2004; 304(5676): 1497-500.

Non-limiting examples of small molecule EGFR inhibitors include any ofthe EGFR inhibitors described in the following patent publications, andall pharmaceutically acceptable salts and solvates of said EGFRinhibitors: European Patent Application EP 520722, published Dec. 30,1992; European Patent Application EP 566226, published Oct. 20, 1993;PCT International Publication WO 96/33980, published Oct. 31, 1996; U.S.Pat. No. 5,747,498, issued May 5, 1998; PCT International Publication WO96/30347, published Oct. 3, 1996; European Patent Application EP 787772,published Aug. 6, 1997; PCT International Publication WO 97/30034,published Aug. 21, 1997; PCT International Publication WO 97/30044,published Aug. 21, 1997; PCT International Publication WO 97/38994,published Oct. 23, 1997; PCT International Publication WO 97/49688,published Dec. 31, 1997; European Patent Application EP 837063,published Apr. 22, 1998; PCT International Publication WO 98/02434,published Jan. 22, 1998; PCT International Publication WO 97/38983,published Oct. 23, 1997; PCT International Publication WO 95/19774,published Jul. 27, 1995; PCT International Publication WO 95/19970,published Jul. 27, 1995; PCT International Publication WO 97/13771,published Apr. 17, 1997; PCT International Publication WO 98/02437,published Jan. 22, 1998; PCT International Publication WO 98/02438,published Jan. 22, 1998; PCT International Publication WO 97/32881,published Sep. 12, 1997; German Application DE 19629652, published Jan.29, 1998; PCT International Publication WO 98/33798, published Aug. 6,1998; PCT International Publication WO 97/32880, published Sep. 12,1997; PCT International Publication WO 97/32880 published Sep. 12, 1997;European Patent Application EP 682027, published Nov. 15, 1995; PCTInternational Publication WO 97/02266, published Jan. 23, 1997; PCTInternational Publication WO 97/27199, published Jul. 31, 1997; PCTInternational Publication WO 98/07726, published Feb. 26, 1998; PCTInternational Publication WO 97/34895, published Sep. 25, 1997; PCTInternational Publication WO 96/31510′, published Oct. 10, 1996; PCTInternational Publication WO 98/14449, published Apr. 9, 1998; PCTInternational Publication WO 98/14450, published Apr. 9, 1998; PCTInternational Publication WO 98/14451, published Apr. 9, 1998; PCTInternational Publication WO 95/09847, published Apr. 13, 1995; PCTInternational Publication WO 97/19065, published May 29, 1997; PCTInternational Publication WO 98/17662, published Apr. 30, 1998; U.S.Pat. No. 5,789,427, issued Aug. 4, 1998; U.S. Pat. No. 5,650,415, issuedJul. 22, 1997; U.S. Pat. No. 5,656,643, issued Aug. 12, 1997; PCTInternational Publication WO 99/35146, published Jul. 15, 1999; PCTInternational Publication WO 99/35132, published Jul. 15, 1999; PCTInternational Publication WO 99/07701, published Feb. 18, 1999; and PCTInternational Publication WO 92/20642 published Nov. 26, 1992.Additional non-limiting examples of small molecule EGFR inhibitorsinclude any of the EGFR inhibitors described in Traxler, P., 1998, Exp.Opin. Ther. Patents 8(12):1599-1625.

Antibody-based EGFR inhibitors include any anti-EGFR antibody orantibody fragment that can partially or completely block EGFR activationby its natural ligand. Non-limiting examples of antibody-based EGFRinhibitors include those described in Modjtahedi, H., et al., 1993, Br.J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645;Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, S. M., etal., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., et al., 1999,Cancer Res. 59:1236-1243. Thus, the EGFR inhibitor can be monoclonalantibody Mab E7.6.3 (Yang, 1999 supra), or Mab C₂₂₅ (ATCC Accession No.HB-8508), or an antibody or antibody fragment having the bindingspecificity thereof.

MEK inhibitors include, but are not limited to, CI-1040, AZD6244,PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, andPD-325901.

PI3K inhibitors include, but are not limited to, wortmannin,17-hydroxywortmannin analogs described in WO 06/044453,4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine(also known as GDC 0941 and described in PCT Publication Nos. WO09/036,082 and WO 09/055,730),2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile(also known as BEZ 235 or NVP-BEZ 235, and described in PCT PublicationNo. WO 06/122806),(S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one(described in PCT Publication No. WO 2008/070740), LY294002(2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from AxonMedchem), PI 103 hydrochloride(3-[4-(4-morpholinylpyrido-[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl]phenolhydrochloride available from Axon Medchem), PIK 75(N′-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazidehydrochloride available from Axon Medchem), PIK 90(N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamideavailable from Axon Medchem), GDC-0941 bismesylate(2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidinebismesylate available from Axon Medchem), AS-252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dioneavailable from Axon Medchem), and TGX-221(7-Methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-oneavailable from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitorsinclude demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126,INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615,ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477,CUDC-907, and AEZS-136.

AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1)(Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2(inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. 385 (Pt. 2),399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91,1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700);indole-3-carbinol and derivatives thereof (e.g., U.S. Pat. No.6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S);perifosine (e.g., interferes with Akt membrane localization;Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004);phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis(2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCNor API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res.64, 4394-9).

TOR inhibitors include, but are not limited to, inhibitors includeAP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus,ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30and Torin 1. Other TOR inhibitors in FKBP12 enhancer; rapamycins andderivatives thereof, including: CCI-779 (temsirolimus), RAD001(Everolimus; WO 9409010) and AP23573; rapalogs, e.g. as disclosed in WO98/02441 and WO 01/14387, e.g. AP23573, AP23464, or AP23841;40-(2-hydroxyethyl)rapamycin,40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also calledCC1779), 40-epi-(tetrazolyt)-rapamycin (also called ABT578),32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapanycin, and otherderivatives disclosed in WO 05005434; derivatives disclosed in U.S. Pat.No. 5,258,389, WO 94/090101, WO 92/05179, U.S. Pat. No. 5,118,677, U.S.Pat. No. 5,118,678, U.S. Pat. No. 5,100,883, U.S. Pat. No. 5,151,413,U.S. Pat. No. 5,120,842, WO 93/111130, WO 94/02136, WO 94/02485, WO95/14023, WO 94/02136, WO 95/16691, WO 96/41807, WO 96/41807 and U.S.Pat. No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g.,WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. ProvisionalApplication No. 60/528,340).

Immune therapies include, but are not limited to, anti-PD-1 agents,anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40agents. Exemplary anti-PD-1 antibodies and methods for their use aredescribed by Goldberg et al., Blood 110(1): 186-192 (2007), Thompson etal., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al.,International Application No. PCT/JP2006/309606 (publication no. WO2006/121168 A1), each of which are expressly incorporated by referenceherein. include: Yervoy™ (ipilimumab) or Tremelimumab (to CTLA-4),galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1), AMP224 (toB7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1), MEDI-570 (to ICOS),AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to LAG-3), BMS-663513 (toCD137), PF-05082566 (to CD137), CDX-1127 (to CD27), anti-OX40(Providence Health Services), huMAbOX40L (to OX40L), Atacicept (toTACI), CP-870893 (to CD40), Lucatumumab (to CD40), Dacetuzumab (toCD40), Muromonab-CD3 (to CD3), Ipilumumab (to CTLA-4). Immune therapiesalso include genetically engineered T-cells (e.g., CAR-T cells) andbispecific antibodies (e.g., BiTEs).

GITR agonists include, but are not limited to, GITR fusion proteins andanti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, aGITR fusion protein described in U.S. Pat. No. 6,111,090box.c, EuropeanPatent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g.,in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat.No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886,European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683,PCT Publication No.: WO 2013/039954, PCT Publication No.: WO2005/007190,PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808,PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720,PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCTPublication No.: WO 2005/115451, U.S. Pat. No. 7,618,632, and PCTPublication No.: WO 2011/051726.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the disclosure will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of thedisclosure and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentdisclosure can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the disclosure and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

As one aspect of the present invention contemplates the treatment of thedisease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes, and bags. In some embodiments, thekit comprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing health care professional.

EXAMPLES Method 1 Example 1-1:1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one

Step 1: 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate A)

A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (3.91 g, 16.71 mmol,Apollo Scientific Ltd., Stockport, UK) and N-chlorosuccinimide (1.36 mL,16.7 mmol) in N,N-dimethylformamide (33 mL) was stirred at 70° C. for 20h. The reaction mixture was then allowed to cool to rt, ice water (40mL) was added, and the resulting mixture was stirred for 1 h. Theresulting precipitate was collected by filtration, washed with water,and dried in vacuo to give 2-amino-4-bromo-5-chloro-3-fluorobenzoicacid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (1H, d, J=2.0 Hz), 6.48-7.23 (2H,br s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −119.70 (1F, s). m/z (ESI, +ve)270.0 (M+H)⁺.

Step 2: 2-Amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B)

Ammonium chloride (1.10 g, 20.6 mmol) and diisopropylethylamine (5.13mL, 29.5 mmol) were sequentially added to a mixture of2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate A, 3.96 g,14.7 mmol) and TBTU (4.97 g, 15.5 mmol, Advanced ChemTech, Louisville,Ky., USA) in N,N-dimethylformamide (30 mL), and the resulting wasstirred at rt for 30 min. The reaction mixture was then added tosaturated aqueous sodium bicarbonate and stirred for 15 min. Theresulting precipitate was collected by filtration, washed with water,and dried in vacuo to give 2-amino-4-bromo-5-chloro-3-fluorobenzamide.¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (1H, br s), 7.72 (1H, d, J=2.0 Hz),7.47 (1H, br s), 6.86 (2H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −120.79 (1F,s). m/z (ESI, +ve) 268.9 (M+H)⁺.

Step 3: 2-Amino-4-bromo-5-chloro-3-fluorobenzothioamide

Lawesson's reagent (2.81 g, 6.95 mmol) was added to2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B, 3.10 g,11.59 mmol) in THF (77 mL), and the resulting mixture was stirred at rtfor 1 h. The reaction mixture was then diluted with EtOAc (75 mL) andsequentially washed with aqueous 2 M HCl (50 mL), saturated aqueoussodium bicarbonate solution (50 mL), and brine (50 mL). The organicextract was then dried over Na₂SO₄, collected by filtration, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0-3% MeOH in DCM) provided2-amino-4-bromo-5-chloro-3-fluorobenzothioamide: ¹H NMR (400 MHz,DMSO-d₆) δ 9.93-10.15 (1H, m), 9.63 (1H, br s), 7.28 (1H, d, J=1.96 Hz),6.34 (2H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −119.52 (1F, s). m/z (ESI,+ve) 284.8 (M+H)⁺.

Step 4: 6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine

Hydrogen peroxide (30% by wt. in water, 2.93 mL, 28.7 mmol) was addeddropwise to an ice-cooled solution of2-amino-4-bromo-5-chloro-3-fluorobenzothioamide (2.71 g, 9.55 mmol) inpyridine (32 mL), and the resulting mixture was subsequently allowed towarm to rt and stir for 24 h. Water (50 mL) was added, and theprecipitated solid was collected by filtration, washed with water, anddried in vacuo to give6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine: ¹H NMR (400 MHz,DMSO-d₆) δ 8.12-8.26 (2H, m), 7.95-8.06 (1H, m). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −114.32 (1F, s). m/z (ESI, +ve) 283.0 (M+H)⁺.

Step 5: 6-Bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole (IntermediateC)

To an ice-cooled mixture of6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-amine (2.47 g, 8.78 mmol),water (12 mL), and concentrated hydrochloric acid (37 wt %, 12 mL, 395mmol) was slowly added a solution of sodium nitrite (0.788 g, 11.4 mmol)in water (2.0 mL). The resulting mixture was stirred at 0° C. for 2.5 h,and a mixture of copper (I) chloride (1.39 g, 14.1 mmol) in concentratedhydrochloric (37 wt %, 12 mL, 395 mmol) was then added at 0° C. Thereaction mixture was subsequently allowed to warm to rt and stir for 20h. The reaction mixture was diluted with water (50 mL), and theprecipitated solid was collected by filtration and dried in vacuo. Thecollected material was taken up in (3:1) DCM:MeOH (200 mL) andsequentially washed with water (200 mL) and brine (100 mL). The organiclayer was then dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-20% EtOAc inheptane) gave 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole: ¹H NMR(400 MHz, DMSO-d₆) δ 7.99 (1H, d, J=1.57 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆)δ −111.48 (1F, s). m/z (ESI, +ve) 425.0 (M+H)⁺.

Step 6: tert-Butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D)

A mixture of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole(Intermediate C, 150 mg, 0.497 mmol) and 1-Boc-piperazine (204 mg, 1.09mmol) in N,N-dimethylformamide (2.0 mL) was stirred at rt for 20 h. Thereaction mixture was then adsorbed onto silica gel andchromatographically purified (silica gel, 0-20% EtOAc in heptane) toprovide tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (1H, d, J=1.56 Hz), 3.68-3.79 (4H,m), 3.40-3.51 (4H, m), 1.26 (9H, s). m/z (ESI, +ve) 451.8 (M+H)⁺.

Step 7: tert-Butyl4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D, 111 mg, 0.247 mmol), 2-bromo-5-methoxybenzene boronicacid (0.114 mL, 0.494 mmol), sodium carbonate (0.041 mL, 0.988 mmol),and tetrakis(triphenylphosphine)palladium (14.3 mg, 0.012 mmol) in1,4-dioxane (1.6 mL) and water (0.4 mL) was heated at 90° C. for 21 h.The reaction mixture then concentrated in vacuo, adsorbed onto silicagel, and purified by column chromatography (silica gel, 0-20% (3:1)EtOAc/EtOH in heptane) to furnish tert-butyl4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate:m/z (ESI, +ve) 558.1 (M+H)⁺.

Step 8:1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one

Hydrogen chloride (4M in 1,4-dioxane, 2.0 mL, 8.0 mmol) was added to amixture of tert-butyl4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(107 mg, 0.192 mmol) and methanol (2.0 mL), and the resulting mixturewas stirred at rt for 1 h. The reaction mixture was then concentrated invacuo to give6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazole:m/z (ESI, +ve) 458.0 (M+1)+.

To this material (88 mg) was added N,N-diisopropylethylamine (0.101 mL,0.578 mmol) in dichloromethane (2 mL), and the resulting mixture wascooled to 0° C. Acryloyl chloride (0.26 M in DCM, 0.75 mL, 0.19 mmol)was added, and the resulting mixture was stirred at 0° C. for 10 min.The reaction mixture was concentrated in vacuo to provide1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one:m/z (ESI, +ve) 512.0 (M+H)⁺.

For compounds without a methyl ether protecting group, the crudematerial was purified at this stage. For compounds bearing a methylether protecting group, the crude material was used in the nexttransformation without purification:

The resulting1-(4-(6-(2-bromo-5-methoxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-onewas taken up in 1,2-dichloroethane (2.0 mL) and cooled to 0° C. Borontribromide solution (1.0 M in hexanes, 0.97 mL, 0.97 mmol) was added,and the resulting mixture was stirred at 0° C. for 1 h. The reactionmixture was then added to saturated aqueous sodium bicarbonate (2.0 mL)and extracted with (2:1) DCM/MeOH (10 mL). The organic extract was driedover Na₂SO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0-3% MeOH in DCM) provided1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (br s, 1H), 8.04 (s, 1H), 7.55 (d,J=8.7 Hz, 1H), 6.81-6.94 (m, 2H), 6.79 (d, J=2.9 Hz, 1H), 6.19 (dd,J=16.7, 2.2 Hz, 1H), 5.77 (dd, J=10.5, 2.2 Hz, 1H), 3.87 (br d, J=19.5Hz, 4H), 3.63 (br t, J=5.1 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.16(1F, s). m/z (ESI, +ve) 498.0 (M+H)⁺

TABLE 1(a) Compounds 1-2 to 1-28 were prepared following the proceduredescribed in Method 1, Steps 1-8, above as follows: Method Ex.# ChemicalStructure Name changes Reagent 1-2

1-(4-(5-chloro-7- fluoro-6-(1H-indol- 3-yl)-2,1- benzothiazol-3-yl)-1-piperazinyl)-2- propen-1-one Omit step 8-3 Step 7: (1-(tert-butoxycarbonyl)-1h- indol-3-yl)boronic acid (Combi-blocks Inc. SanDiego, CA, USA), Step 8-1: TFA/DCM 1-3

1-(4-(5-chloro-6-(2- fluoro-6- hydroxyphenyl)- 2,1-benzothiazol-3-yl)-1- piperazinyl)-2- propen-1-one Omit step 8-3 Step 7: (3-methoxynaphthalen- 1-yl)boronic acid, Cs₂CO₃, 100° C., Step 8-1: TFA/DCM1-4

1-(4-(5-chloro-6-(3- methoxy-1- naphthalenyl)-2,1- benzothiazol-3-yl)-1-piperazinyl)-2- propen-1-one — Step 7: (3- methoxynaphthalen-l-yl)boronic acid, Cs₂CO₃, 100° C., Step 8-1: TFA/DCM 1-5

1-(4-(5-chloro-6-(2- fluoro-6- methoxyphenyl)- 2,1-benzothiazol-3-yl)-1-piperazinyl)- 2-propen-1-one — Step 7: (2-fluoro-6- methoxyphenyl)boronic acid, Cs₂CO₃, 100° C., Step 8-1: TFA/DCM 1-6

1-(4-(5-chloro-6-(2- fluoro-6- hydroxyphenyl)- 2,1-benzothiazol-3-yl)-1-piperazinyl)- 2-propen-1-one — Step 7: (2-fluoro-6- methoxyphenyl)boronic acid, Cs₂CO₃, 100° C., Step 8-1: TFA/DCM 1-7

1-((3R)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-(hydroxymethyl)- 1-piperazinyl)-2- propen-1-one —Step 6: (3R)-1-(tert- butoxycarbonyl)-3- (hydroxymethyl) piperazine(Synthonix Inc., Wake Forest, NC, USA), Step 7: (3- methoxynaphthalen-1-yl)boronic acid (Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1:TFA/DCM 1-8

1-4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-ethyl-1- piperazinyl)-2- propen-1-one — Step 6:tert-butyl 3- ethylpiperazine-1- carboxylate (Accel Pharmtech LLC, EastBrunswick, NJ, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid(Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM

1-9

N-(1-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 2-methyl-3- azetidinyl)-2- propenamide — Step 6:tert-butyl (2- methylazetidin-3- yl)carbamate (PharmaBlock, Nanjing,China), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc.Arlington Heights, IL, USA), Step 8-1: TFA/DCM

1-10

1-((3S)-4-(5- chloro-7-fluoro-6- (5-methyl-1H- indazol-4-yl)-2,1-benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one Omit step8-3 Step 6: (S)-4-n-boc- 2-methyl piperazine (CNH Technologies, Inc.,Woburn, MA, USA), Step 7: 4-borono-5-methyl- 1h-indazole (Ark Pharm Inc.Arlington Heights, IL, USA.), Step 8-1: TFA/DCM 1-11

1-((3S)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-(2-hydroxyethyl)- 1-piperazinyl)-2- proper-1-one —Step 6: (S)-tert-butyl 3-(2- hydroxyethyl) piperazine-1- carboxylate(Activate Scientific GmbH, Prien, Germany), Step 7: (3-methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington Heights,IL, USA), Step 8-1: TFA/DCM 1-12

4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 1-(2-propenoyl)-2- piperazine- carboxamide — Step 6:piperazine- 2-carboxamide (Enamine, Kiev, Ukraine), Step 7: (3-methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington Heights,IL, USA), Step 8-1: TFA/DCM

1-13

1-(4-(5-chloro-7- fluoro-6-(2- methoxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 1-piperazinyl)-2- propen-1-one Omit step 8-3 Step 7:(2- methoxynaphthalen- 1-yl)boronic acid, Cs₂CO₃, 100° C., Step 8-1:TFA/DCM 1-14

l-(4-(5-chloro-7- fluoro-6-(2- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 1-piperaziny)-2- propen-1-one — Step 7: (2-methoxynaphthalen- 1-yl)boronic acid, Cs₂CO₃, 100° C., Step 8-1: TFA/DCM1-15

l-((3S)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-(hydroxymethyl)- 1-piperazinyl)-2- propen-1-one —Step 6: (3S)-1-boc- 3-(hydroxymethyl)- piperazine (Combi- blocks Inc.,San Diego, CA, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid,Step 8-1: TFA/DCM 1-16

1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 2-(hydroxymethyl)- 1-piperazinyl)-2- propen-1-one —Step 6: tert-butyl 3- (((tert- butyldimethylsilyl)oxy)methyl)piperazine- 1-carboxylate^(i), Step 7: (3- methoxynaphthalen-1-yl)boronic acid, Step 8-1: TFA/DCM

1-17

1-((1R,5S)-3-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3,8- diazabicyclo[3.2.1] octan-8-yl)-2- propen-1-one— Step 6: 8-boc-3,8- diaza- bicyclo[3.2.1]octane (Chem-ImpexInternational, Inc. Wood Dale, IL, USA), Step 7: (3- methoxynaphthalen-1-yl)boronic acid (Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1:TFA/DCM 1-18

1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-(hydroxymethyl)- 1-piperazinyl)-2- propen-1-one —Step 6: 4-n-boc-2- hydroxymethyl- piperazine (AstaTech, Inc., Bristol,PA, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark PharmInc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM

1-19

1-((3S)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one — Step 6:(S)-4-n-boc- 2-methyl piperazine (CNH Technologies, Inc., Woburn, MA,USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc.Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-20

1-(3-((5-chloro-7 fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)amino)-1- azetidinyl)-2- propen-1-one — Step 6:1-boc-3- aminoazetidine (Alfa Aesar, Haver Hill MA, USA), Step 7: (3-methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc. Arlington Heights,IL, USA), Step 8-1: TFA/DCM 1-21

1-((3R)-4-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one — Step 6:(R)-4-n-boc- 2-methyl-piperazine (CNH Technologies, Inc., Woburn, MA,USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark Pharm Inc.Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-22

N-((3R)-1-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-pyrrolidinyl)-2- propenamide Step 6: (3R)-(-)-3-tert- butoxycarbonylamino pyrrolidine (Oakwood Products, Inc. Estill,SC, USA), Step 7: (3- methoxynaphthalen- 1-yl)boronic acid (Ark PharmInc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-23

N-((3R)-1-(5- chloro-7-fluoro-6- (3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)- 3-piperidinyl)-2- propenamide Step 6: (R)-tert-butyl piperidin-3- ylcarbamate (Combi-blocks Inc., San Diego, CA, USA),Step 7: (3- methoxynaphthalen- l-yl)boronic acid (Ark Pharm Inc.Arlington Heights, IL, USA), Step 8-1: TFA/DCM 1-28

1-(4-(5-chloro-7- fluoro-6-(2-fluoro- 5- hydroxyphenyl)benzo[c]isothiazol-3- yl)piperazin-1- yl)prop-2-en-1-one Step 7:(2-fluoro-5- methoxyphenyl) boronic acid (Combi- blocks Inc., San Diego,CA, USA), K₂CO₃, Pd(dppf)Cl₂ · DCM, 100° C. Step 8-1: TFA/DCM

Method 2 Example 2-1:1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one

Step 1: 2-Amino-6-bromo-5-chloronicotinic acid

N-Chlorosuccinimide (2.78 g, 20.8 mmol) was added to a solution of2-amino-6-bromonicotinic acid (4.51 g, 20.8 mmol, Ark Pharm Inc.Arlington Heights, Ill., USA) in DMF (75 mL), and the resulting mixturewas heated at 70° C. for 2.5 h. Heating was then stopped, and stirringwas continued for 16 h. The reaction mixture was subsequently pouredinto ice water. After the ice had melted, the resulting slurry wasfiltered through a fritted glass funnel. The collected solids wereair-dried, providing 2-amino-6-bromo-5-chloronicotinic acid: ¹H NMR (400MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.64 (br. s, 2H). m/z (ESI, +ve) 250.9(M+H)⁺.

Step 2: tert-Butyl4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate

To a solution of 2-amino-6-bromo-5-chloronicotinic acid (1.12 g, 4.5mmol) in DMF (14 mL) was added TBTU (1.93 g, 6.0 mmol). After 5 min, thereaction was sequentially treated with 1-Boc-piperazine (912 mg, 4.9mmol) and DIPEA (2.33 mL, 13.4 mmol). The resulting solution was stirredat rt for 25 h, saturated aqueous NaHCO₃ solution (75 mL) was added, andthe resulting mixture was extracted with DCM. The organic layer wasseparated and sequentially washed with water (2×), dried over anhydroussodium sulfate, and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0 to 7% MeOH in DCM) furnished tert-butyl4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate: ¹H NMR(400 MHz, DMSO-d₆) δ 7.58 (s, 1H), 6.66 (s, 2H), 3.33 (s, 8H), 1.40 (s,9H). m/z (ESI, +ve) 419.0 (M+H)⁺.

Step 3: tert-Butyl4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate

Lawesson's reagent (353 mg, 0.87 mmol) was added to a solution oftert-butyl4-(2-amino-6-bromo-5-chloronicotinoyl)piperazine-1-carboxylate (610 mg,1.45 mmol) in THF (7.5 mL), and the resulting solution was stirred as50° C. for 2.5 h. The reaction mixture was then allowed to cool to rtand sequentially treated with water (10 mL) and aqueous 1 N HCl (4 mL).The resulting mixture was extracted with EtOAc (2×), and the combinedextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0-6% MeOH in DCM) provided tert-butyl4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate:¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (s, 1H), 6.58 (br. s, 2H), 4.30 (ddd,J=13.3, 6.3, 3.3 Hz, 1H), 4.01-4.13 (m, 2H), 3.68-3.77 (m, 1H),3.51-3.59 (m, 1H), 3.40-3.50 (m, 3H), 1.41 (s, 9H). m/z (ESI, +ve) 434.9(M+H)⁺.

Step 4: tert-Butyl4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate

NCS (116 mg, 0.87 mmol) was added to a solution of tert-butyl4-(2-amino-6-bromo-5-chloropyridine-3-carbonothioyl)piperazine-1-carboxylate(343 mg, 0.79 mmol) in THF (8 mL), and the resulting solution wasstirred at rt for 20 min. A mixture of water (10 mL) and 1 M aqueoussodium sulfite (5 mL) was then added, and the resulting mixture wasextracted with EtOAc (2×). The combined extracts were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 4% MeOH inDCM) provided tert-butyl4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate:¹H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (s, 1H), 3.69-3.80 (m, 4H),3.50-3.57 (m, 4H), 1.51 (s, 9H). m/z (ESI, +ve) 389.0 (M+H)⁺.

Step 5: tert-Butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5,6-dichloroisothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate(154 mg, 0.36 mmol), (3-methoxynaphthalen-1-yl)boronic acid (287 mg,1.42 mmol), and cesium carbonate (463 mg, 1.42 mmol) in 1,4-dioxane (8mL) and water (2 mL) was sparged with argon before addingtetrakis(triphenylphosphine)palladium (41 mg, 0.04 mmol). The reactionmixture was again sparged with argon, then heated in a sealed tube at100° C. for 25 h. After cooling to rt, the reaction mixture was dilutedwith brine (40 mL) and extracted with EtOAc (2×). The combined extractswere dried over sodium sulfate, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-3.5% MeOH inDCM) gave tert-butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate:m/z (ESI, +ve) 511.1 (M+H)⁺.

Step 6:5-Chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridine

Trifluoroacetic acid (560 □L, 7.6 mmol) was added to a solution oftert-butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazine-1-carboxylate(155 mg, 0.30 mmol) in DCM (6 mL), and the resulting solution wasstirred at rt for 2.3 h, then concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0-25% MeOH in DCM) furnished5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridineas a TFA salt: ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 7.94 (d, J=8.2Hz, 1H), 7.46-7.53 (m, 2H), 7.31 (d, J=3.7 Hz, 2H), 7.19 (d, J=2.4 Hz,1H), 3.95 (s, 3H), 3.76-3.83 (m, 4H), 3.35-3.43 (m, 4H). m/z (ESI, +ve)411.0 (M+H)+.

Step 7:1-(4-(5-Chloro-6-(3-methoxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one

To an ice-cooled slurry of5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)isothiazolo[3,4-b]pyridine(TFA salt; 100 mg, 0.19 mmol) in DCM (5 mL) was sequentially added DIPEA(100 □L, 0.57 mmol) and acryloyl chloride (23 □L, 0.29 mmol). Theresulting solution was stirred at 0° C. for 70 min, and saturatedaqueous NaHCO₃ solution (15 mL) was added. The resulting mixture wasextracted with DCM (3×), and the combined extracts were dried oversodium sulfate, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 7% MeOH in DCM) provided1-(4-(5-chloro-6-(3-methoxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 7.93 (d, J=8.2 Hz, 1H),7.45-7.54 (m, 2H), 7.25-7.39 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 6.86 (dd,J=16.7, 10.3 Hz, 1H), 6.19 (dd, J=16.7, 2.3 Hz, 1H), 5.77 (dd, J=10.5,2.3 Hz, 1H), 3.94 (s, 3H), 3.81-3.94 (m, 4H), 3.69-3.76 (m, 4H). m/z(ESI, +ve) 465.0 (M+H)⁺.

Step 8:1-(4-(5-Chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one

Boron tribromide (1.0 M in hexanes, 400 □L, 0.40 mmol) was added(dropwise) to an ice-cooled solution of1-(4-(5-chloro-6-(3-methoxynaphthalen-1-yl)isothiazolo[3,4-b]pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one(37.3 mg, 0.08 mmol) in 1,2-dichloroethane (4 mL), and the resultingmixture was stirred at 0° C. for 2.3 h. Saturated aqueous NaHCO₃solution (5 mL) was then added, and the resulting mixture was extractedwith (4:1) DCM:MeOH (2×). The combined extracts were dried over sodiumsulfate, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0-6% MeOH in DCM) provided1-(4-(5-chloro-6-(3-hydroxy-1-naphthalenyl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-1-piperazinyl)-2-propen-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (br. s, 1H), 8.72 (s, 1H), 7.79 (d,J=8.6 Hz, 1H), 7.42 (t, J=7.1 Hz, 1H), 7.17-7.28 (m, 3H), 7.09 (d, J=2.1Hz, 1H), 6.86 (dd, J=16.7, 10.5 Hz, 1H), 6.19 (dd, J=16.7, 2.3 Hz, 1H),5.74-5.79 (m, 1H), 3.81-3.95 (m, 4H), 3.68-3.76 (m, 4H). m/z (ESI, +ve)451.0 (M+H)⁺.

TABLE 2 Compounds 2-2 to 2-6 were prepared following the proceduredescribed in Method 2, Steps 1-8, above as follows: Method Ex.# ChemicalStructure Name changes Reagents 2-2

1-(4-(5-chloro-6- (2-fluoro-6- methoxyphenyl) [1,2]thiazolo[3,4-b]pyridin-3-yl)-3- methyl-1- piperazinyl)-2- propen-1-one Omit Step 8Step 2: 1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA,USA), Step 4: N- bromosuccinimide, Step 5: 2-fluoro-6- methoxyphenylboronic acid

2-3

1-(4-(5-chloro-6- (2-fluoro-6- hydroxyphenyl)[1, 2]thiazolo[3,4-b]pyridin-3-yl)-3- methyl-1- piperazinyl)-2- propen-1-one — Step 2:1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA, USA), Step4: N- bromosuccinimide, Step 5: 2-fluoro-6- methoxyphenyl boronic acid

2-4

1-(4-(5-chloro-6- (3-methoxy-1- naphthalenyl)[1,2] thiazolo[3,4-b]pyridin-3-yl)-3- methyl-1- piperazinyl)-2- propen-1-one Omit Step 8Step 2: 1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA,USA), Step 4: N- bromosuccinimide

2-5

1-(4-(5-chloro-6- (3-hydroxy-1- naphthalenyl)[1,2] thiazolo[3,4-b]pyridin-3-yl)-3- methyl-1- piperazinyl)-2- propen-1-one — Step 2:1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA, USA), Step4: N- bromosuccinimide

2-6

1-(4-(5-chloro-6- (5-methyl-1H- indazol-4- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)- 3-methyl-1- piperazinyl)-2- propen-1-one Omit Step 8Step 2: 1-Boc-3- methylpiperazine (Accela ChemBio Inc. San Diego, CA,USA), Step 4: N- bromosuccinimide, Step 5: 4-borono-5-methyl-1h-indazole (Ark Pharm Inc. Arlington Heights, IL, USA)

2-7

1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)-3,5-dimethyl- 1-piperazinyl)-2- propen-1-one — Step1: 2-amino-4- bromo-3- fluorobenzoic acid (Apollo Scientific Ltd.,Stockport, UK), Step 2: 1-boc-3,5- dimethylpiperazine (Combi-blocksInc., San Diego, CA, USA), Step 7: (3- methoxynaphthalen-1- yl)boronicacid (Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM

2-8

1-(4-(5-chloro-7- fluoro-6-(5- methyl-1H- indazol-4-yl)-2,1-benzothiazol-3- yl)-3- (difluoromethyl)- 1-piperazinyl)-2- propen-1-one— Step 1: 2-amino-4- bromo-3- fluorobenzoic acid (Apollo ScientificLtd., Stockport, UK), Step 2: tert-butyl 3- (difluoromethyl)piperazine-1-carboxylate (Enamine, Kiev, Ukraine), Step 7: (5-methyl-1H-indazol-4- yl)boronic acid (Combi-Blocks, Inc.), Step 8-1:TFA/DCM

2-9

1-(4-(5-chloro-7- fluoro-6-(2-fluoro- 6-hydroxyphenyl)-2,1-benzothiazol- 3-yl)-3- (difluoromethyl)- 1-piperazinyl)-2-propen-1-one Step 8-3 performed prior to steps 8-2 Step 1: 2-amino-4-bromo-3- fluorobenzoic acid (Apollo Scientific Ltd., Stockport, UK),Step 2: tert-butyl 3- (difluoromethyl) piperazine-1-carboxylate(Enamine, Kiev, Ukraine), Step 7: 2- fluoro-6-methoxy- phenylboronicacid (Accela ChemBio Inc. San Diego, CA, USA), Step 8-1: TFA/DCM

2-10

1-(4-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)-3-(2- propanyl)-1- piperazinyl)-2- propen-1-one —Step 1: 2-amino-4- bromo-3- fluorobenzoic acid (Apollo Scientific Ltd.,Stockport, UK), Step 2: 1-boc-3- isopropyl-piperazine (Ark Pharm Inc.Arlington Heights, IL, USA), Step 7: (3- methoxynaphthalen-1- yl)boronicacid (Ark Pharm Inc. Arlington Heights, IL, USA), Step 8-1: TFA/DCM

Method 3 Example 3-1:1-(4-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one

Step 1:1-(4-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one

0.2 M acryloyl chloride in DCM (1.240 mL, 0.248 mmol) was added to anice-cooled solution of6-bromo-5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate D, 87 mg, 0.248 mmol) and N,N-diisopropylethylamine (0.129mL, 0.744 mmol) in dichloromethane (2.3 mL), and the resulting mixturewas stirred at 0° C. for 10 min. The mixture was then concentrated invacuo, and the residue was sonicated in MeOH (2 mL). The suspended solidwas collected by filtration, washed with MeOH, and dried in vacuo toprovide1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (1H, d, J=1.56 Hz), 6.84 (1H, dd,J=10.47, 16.73 Hz), 6.17 (1H, dd, J=2.35, 16.63 Hz), 5.66-5.82 (1H, m),3.73-3.93 (4H, m), 3.55-3.67 (4H, m). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−113.39 (s, 1F). m/z (ESI, +ve) 405.8 (M+H)⁺.

Step 2:1-(4-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate E)

A mixture of1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate D, 79 mg, 0.20 mmol), (3-methoxynaphthalen-1-yl)boronicacid (47.3 mg, 0.234 mmol), tetrakis(triphenylphosphine)palladium (22.5mg, 0.020 mmol) and sodium carbonate (83 mg, 0.78 mmol) in water (0.500mL) and 1,4-dioxane (2.0 mL) was heated at 100° C. for 16 h. Thereaction mixture was then adsorbed onto silica gel andchromatographically purified (silica gel, 0-3% MeOH in DCM) to give1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one: m/z (ESI, +ve) 482.0 (M+H)⁺.

Step 3:1-(4-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one

Boron tribromide (1.0M in hexanes, 0.664 mL, 0.664 mmol) was added to anice-cooled solution of1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one(64 mg, 0.13 mmol) in 1,2-dichloroethane (2.0 mL), and the resultingmixture was stirred at 0° C. for 1 h. The reaction mixture was thenadded to saturated aqueous sodium bicarbonate (2.0 mL) and the resultingmixture was extracted with (2:1) DCM:MeOH (10 mL). The organic extractwas dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-3% MeOH inDCM) gave1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 9.90-10.04 (1H, m), 8.10 (1H, s), 7.80 (1H,d, J=8.41 Hz), 7.43 (1H, ddd, J=1.96, 6.11, 8.17 Hz), 7.16-7.31 (3H, m),7.07 (1H, d, J=2.35 Hz), 6.87 (1H, dd, J=10.47, 16.73 Hz), 6.19 (1H, dd,J=2.25, 16.73 Hz), 5.77 (1H, dd, J=2.25, 10.47 Hz), 3.88 (4H, br d,J=19.56 Hz), 3.61-3.72 (4H, m). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.78 (s,1F). m/z (ESI, +ve) 468.0 (M+H)⁺.

Alternate Synthesis of Intermediate E

1-(4-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate E,Alternative Synthesis)

To a solution of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole(Intermediate C, 715 mg, 2.37 mmol) in N,N-dimethylformamide (5.6 mL)was sequentially added a solution of 1-(piperazin-1-yl)prop-2-en-1-onebis(2,2,2-trifluoroacetate) (961 mg, 2.61 mmol, eNovation Chemicals LLC,Bridgewater, N.J., USA) in N,N-dimethylformamide (5.6 mL) andN,N-diisopropylethylamine (1.243 mL, 7.12 mmol). The resulting mixturewas stirred at rt for 1 h and then heated at 50° C. for 22 h. Aftercooling to rt, the reaction mixture was added to ice water (10 mL), andthe resulting precipitate was collected by filtration and washed withwater. The collected solid was adsorbed onto silica gel andchromatographically purified (silica gel, 0-3% MeOH in DCM) to furnish1-(4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one.

TABLE 3 Compounds 3-2 to 3-24 were prepared following the proceduredescribed in Method 3, Steps 1-3, above as follows: Method Ex.# ChemicalStructure Name changes Reagent 3-2

8-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1- piperazinyl)-2,1-benzothiazol-6- yl)-2(1H)- quinolinone Omit step 3 Step 2: 8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)quinolin-2(1H)- one (Chem Shuttle,Hayward, CA, USA), S-Phos Pd G3, aq. K₂CO₃, 1,4- dioxane 3-3

1-(4-(5-chloro-7- fluoro-6-(8- isoquinolinyl)-2,1- benzothiazol-3-yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2: 8-boronoisoquinoline (Frontier Scientific, Inc. Logan, UT, USA) 3-4

5-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1- piperazinyl)-2,1-benzothiazol-6- yl)-2(1H)- quinolinone Omit step 3 Step 2: 5-(4,4.5,5-1etramethyl-1,3,2- dioxaborolan-2- yl)quinolin-2(1h)- one (Ark PharmInc. Arlington Heights. IL, USA) 3-5  

1-(4-(5-chloro-7- fluoro-6-(5- methyl-1H- indazol-4-yl)-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2:4-borono-5- methyl-1h-indazole (Ark Pharm Inc. Arlington Heights, IL,USA) 3-6

1-(4-(5-chloro-7- fiuoro-6-(2-fluoro- 6-hydroxyphenyl)-2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one — Step 2:2-fluoro-6- methoxy- phenylboronic acid (Accela ChemBio Inc. San Diego,CA, USA) 3-7

1-(4-(5-chloro-6- (2,4- difluorophenyl)-7- fluoro-2,1- benzothiazol-3-yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2: (2,4-difluorophenyl) boronic acid (Combi-blocks Inc., San Diego, CA, USA) 3-8

1-(4-(5-chloro-7- fluoro-6-(5- hydroxy-2- methylphenyl)-2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3 Step2: (5-hydroxy- 2- methylphenylboronic acid (Combi-blocks Inc., SanDiego, CA, USA) 3-9

1-(4-(5-chloro-6- (2-chloro-5- methoxyphenyl)- 7-fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2:2-chloro-5- methoxyphenyl boronic acid (Combi-blocks Inc.. San Diego,CA, USA) 3-10

1-(4-(5-chloro-6- (2,4-difluoro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2: 1-boronicacid-2,4-difluoro-5- methoxy-benzene (Combi-blocks Inc., San Diego, CA,USA) 3-11

1-(4-(5-chloro-6- (2-chloro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2: 2-chloro-5-methoxyphenyl boronic acid (Combi-blocks Inc., San Diego, CA. USA) 3-12

1-(4-(6-(5-amino- 2-methylphenyl)- 5-chloro-7-fluoro- 2,1-benzothiazol-3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3 Step 2: (5-amino-2-methylphenyl) boronic acid (Combi-blocks Inc., San Diego, CA, USA) 3-13

N-(3-(5-chloro-7- fluoro-3-(4-(2- propenoyl)-1- piperazinyl)-2,1-benzothiazol-6- yl)-4- methylphenyl) acetamide Omit step 3 Step 2: [5-(acetylamino)-2- methylphenyl] boronic acid (Combi-blocks Inc., SanDiego, CA, USA) 3-14

1-(4-(6-(5-amino- 2-fluorophenyl)-5- chloro-7-fluoro- 2,1-benzothiazol-3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3 Step 2: 2-fluoro-5-aminophenyl boronic acid (Combi-blocks Inc., San Diego, CA, USA) 3-15

1-(4-(6-(5-amino- 2,3- difluorophenyl)-5- chloro-7-fluoro-2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3 Step2: 3-borono- 4,5-difluoroaniline (Combi-blocks Inc., San Diego, CA, USA)3-16

1-(4-(5-chloro-6- (2,3-difluoro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2:2,3-difluoro- 5- methoxyphenylboronic acid (Combi-blocks Inc.. SanDiego. CA. USA) 3-17

1-(4-(5-chloro-6- (2,4-dichloro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2: (2,4-dichloro-5- methoxyphenyl) boronic acid (Combi-blocks Inc., San Diego,CA, USA) 3-18

1-(4-(5-chloro-6- (2-chloro-4- fluoro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2:(2-chloro-4- fluoro-5- methoxyphenyl) boronic acid (Combi-blocks Inc.,San Diego, CA. USA) 3-19

1-(4-(6-(5-amino- 2-chlorophenyl)-5- chloro-7-fluoro- 2,1-benzothiazol-3-yl)-1- piperazinyl)-2- propen-1-one Omit step 3 Step 2: (5-amino-2-chlorophenyl)boronic acid hydrochloride (Combi-blocks Inc., San Diego,CA, USA) 3-20

1-(4-(6-(5-amino- 2,4- dichlorophenyl)-5- chloro-7-fluoro-2,1-benzothiazol- 3-yl)-1- piperazinyl)-2- propen-1-one — Step 2:(5-amino- 2,4- dichlorophenyl) boronic acid (Combi-blocks Inc., SanDiego, CA, USA) 3-21

1-(4-(5-chloro-7- fluoro-6-(4-(2- propanyl)-3- pyridinyl)-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one Omit step 3 Step 2:(4- isopropylpyridin-3- yl)boronic acid (Combi-Phos Catalysts Inc.Trenton, NJ, USA) 3-22

1-(4-(5-chloro-6- (2,3-dichloro-5- hydroxyphenyl)-7- fluoro-2,1-benzothiazol-3- yl)-1-piperazinyl)- 2-propen-1-one — Step 2: 2-(2,3-dichloro-5- methoxyphenyl)- 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane(Anisyn Inc., Kalamazoo. MI, US) 3-23

1-(4-(5-chloro-7- fluoro-6- (naphthalen-1- yl)benzo[c]isothiazol-3-yl)piperazin- 1-yl)prop-2-en-1- one Omit step 3 Step 1-1: TFA/DCM Step2: (1- naphthalyl)boronic acid, Cs₂CO₃, 80° C. 3-24

1-(4-(5-chloro-7- fluoro-6-(quinolin- 8- yl)benzo[c]isothiazol-3-yl)piperazin- 1-yl)prop-2-en-1- one Omit step 3 Step 1-1: TFA/DCM Step2: 8-quinoline boronic acid (Frontier Scientific Inc., Logan UT, USA),Cs₂CO₃, 80° C. 3-25

3-amino-5-(5- chloro-7-fluoro-3- (4-(2-propenoyl)- 1-piperazinyl)-2,1-benzothiazol-6- yl)benzonitrile Omit step 3 Step 1-1: TFA/DCM Step 2:(3-amino-5- cyanophenyl)boronic acid (Combi- blocks Inc., San Diego, CA,USA), S-Phos Pd G3, K₂CO₃, 100° C.

Method 4 Example 4-1:1-(6-(5-Chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Step 1: tert-Butyl6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

A mixture of 6-bromo-3,5-dichloro-7-fluorobenzo[c]isothiazole(Intermediate C, 169 mg, 0.562 mmol) and2-Boc-2,6-diazaspiro[3.3]heptane (212 mg, 1.07 mmol, AstaTech, Inc.,Bristol, Pa., USA) in DMF (3.5 mL) was stirred at rt for 5 h. Ice water(5 mL) was added, and the resulting mixture was stirred for 15 min. Theresulting precipitate was collected by filtration, washed with water,and dried in vacuo to provide tert-butyl6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:¹H NMR (400 MHz, DMSO-d₆) δ 7.52-7.74 (1H, m), 4.55 (4H, s), 4.09 (4H,s), 1.38 (9H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.55 (1F, s). m/z(ESI, +ve) 464.0 (M+1).

Step 2:1-(6-(6-Bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Hydrogen chloride solution (4M in 1,4-dioxane, 5.0 mL, 20 mmol) wasadded to tert-butyl6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(249 mg, 0.538 mmol) in methanol (10 mL), and the resulting mixture wasstirred at rt for 2 h. The reaction mixture was then concentrated invacuo to provide6-bromo-5-chloro-7-fluoro-3-(2,6-diazaspiro[3.3]heptan-2-yl)benzo[c]isothiazole:m/z (ESI, +ve) 363.8 (M+1)⁺.

To this material was added N,N-diisopropylethylamine (0.281 mL, 1.61mmol) in dichloromethane (3.0 mL), and the resulting mixture was cooledto 0° C. Acryloyl chloride (0.2 M in DCM, 2.69 mL, 0.538 mmol) was thenadded, and the resulting mixture was stirred at 0° C. for 10 min. Thereaction mixture was then concentrated in vacuo, and the residue waschromatographically purified (silica gel, 0-10% (3:1) EtOAc/EtOH in DCM)to provide1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (1H, d, J=1.4 Hz), 6.25-6.36 (1H, m),6.10 (1H, dd, J=17.0, 2.3 Hz), 5.64-5.72 (1H, m), 4.58 (4H, s), 4.47(2H, s), 4.18 (2H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.54 (1F, s). m/z(ESI, +ve) 418.0 (M+H)⁺.

Step 3:1-(6-(5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

A mixture of1-(6-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one(102 mg, 0.245 mmol), (3-methoxynaphthalen-1-yl)boronic acid (59.3 mg,0.294 mmol), tetrakis(triphenylphosphine)palladium (28.3 mg, 0.024mmol), and sodium carbonate (104 mg, 0.979 mmol) in water (0.5 mL) and1,4-dioxane (2.0 mL) was heated at 100° C. for 1 h. The reaction mixturewas then adsorbed onto silica gel and chromatographically purified(silica gel, 0-5% MeOH in DCM). The purified material was sonicated inMeOH, and the suspended solid was collected by filtration, washed withMeOH, and dried in vacuo to provide1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (1H, d, J=8.4 Hz), 7.67 (1H, s),7.45-7.57 (2H, m), 7.23-7.36 (2H, m), 7.16 (1H, d, J=2.5 Hz), 6.27-6.39(1H, m), 6.11 (1H, dd, J=17.0, 2.2 Hz), 5.65-5.76 (1H, m), 4.58-4.67(4H, m), 4.50 (2H, s), 4.22 (2H, s), 3.93 (3H, s). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −123.88 (1F, s). m/z (ESI, +ve) 494.0 (M+H)⁺.

Step 4:1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one

Boron tribromide (1.0 M in hexanes, 0.638 mL, 0.638 mmol) was added toice-cooled1-(6-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one(63 mg, 0.128 mmol) in 1,2-dichloroethane (2.0 mL), and the resultingmixture was stirred at 0° C. for 2 h. The reaction mixture was thenadded to saturated aqueous sodium bicarbonate (2.0 mL), and theresulting mixture was extracted with (2:1) DCM:MeOH (10 mL). The organicextract was dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-2% MeOH (with2M ammonia) in DCM) gave1-(6-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 9.82-10.04 (1H, m), 7.79 (1H, d, J=8.2 Hz),7.66 (1H, s), 7.43 (1H, dt, J=8.3, 4.0 Hz), 7.26 (1H, d, J=2.3 Hz), 7.22(2H, d, J=3.7 Hz), 7.05 (1H, d, J=2.3 Hz), 6.26-6.38 (1H, m), 6.12 (1H,dd, J=16.8, 2.2 Hz), 5.66-5.72 (1H, m), 4.58-4.67 (4H, m), 4.50 (2H, s),4.22 (2H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.98 (1F, s). m/z (ESI,+ve) 480.0 (M+H)⁺.

TABLE 4 Compounds 4-2 to 4-9 were prepared following the proceduredescribed in Method 4, Steps 1-4, above as follows: Method Ex.# ChemicalStructure Name changes Reagent 4-2

1-(6-(6-bromo-5- chloro-7-fluoro- 2,1-benzothiazol- 3-yl)-2,6-diazaspiro[3.3] hept-2-yl)-2-propen- 1-one Omit steps 3 & 4 — 4-3

1-(6-(5-chloro-7- fluoro-6-(3- methoxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)-2,6- diazaspiro[3.3] heptan-2-yl)-2- propen-1-oneOmit step 4 — 4-4

N-(1-(6-bromo-5- chloro-7-fluoro- 2,1-benzothiazol- 3-yl)-3-azetidinyl)-2- propenamide Omit steps 3 & 4 Step 1: 3-N- boc-amino-azetidine, HCl salt (Combi-blocks Inc., San Diego. CA, USA) 4-5

N-(1-(5-chloro-7- fluoro-6-(3- methoxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)-3-azetidinyl)- 2-propenainide Omit step 4 Step 1:3-N- boc-amino- azetidine, HCl salt (Combi-blocks Inc., San Diego. CA,USA) 4-6

N-(1-(5-chloro-7- fluoro-6-(3- hydroxy-1- naphthalenyl)-2,1-benzothiazol-3- yl)-3-azetidinyl)- 2-propenamide — Step 1: 3-N-boc-amino- azetidine, HCl salt (Combi-blocks Inc., San Diego, CA, USA)4-7

1-(3-((6-bromo-5- chloro-7-fluoro- 2,1-benzothiazol- 3-yl)amino)-1-azetidinyl)-2- propen-1-one Omit steps 3 & 4 Step 1: 1-boc-3-aminoazetidine (Alfa Aesar, Haver Hill, MA. USA) 4-8

1-((3R)-3-((6- bromo-5-chloro-7- fluoro-2,1- benzothiazol-3-yl)amino)-1- piperidinyl)-2- propen-1-one Omit steps 3 & 4 Step 1:(R)-tert- butyl 3- aminopiperidine- 1-carboxylate (AstaTech, Inc.,Bristol, PA, USA) 4-9

1-((3R)-3-((5- chloro-7-fluoro-6- (3- hydroxynaphthalen- 1-yl)benzo[c]isothiazol-3- yl)amino)piperidin- 1-yl)prop-2-en-1- one — Step 1:(R)-tert- butyl 3- aminopiperidine- 1-carboxylate (AstaTech, Inc.,Bristol, PA, USA)

Method 5 Example 5-1:N-(1-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-azetidinyl)-N-methyl-2-propenamide

Step 1: 2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide

A mixture of (3-methoxynaphthalen-1-yl)boronic acid (2.04 g, 10.1 mmol),2-amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B (1.93 g, 7.20mmol), tetrakis(triphenylphosphine)palladium (0.832 g, 0.720 mmol),sodium carbonate (1.2 mL, 28.8 mmol) in water (9.6 mL), and 1,4-dioxane(38.4 mL) was heated at 90° C. for 2 days. The reaction mixture was thenfiltered through a pad of Celite, washing with EtOAc. The filtrate wasdiluted with saturated aqueous NaHCO₃ (50 mL) and extracted with EtOAc(3×50 mL). The organic extract was washed with brine (30 mL) and driedover Na₂SO₄. The solution was then filtered and the filtratedconcentrated in vacuo. The residue was suspended in MeOH (5 mL), and thesuspended solid collected by filtration, washed with MeOH, and dried togive 2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide.Chromatographic purification of the concentrated filtrate (silica gel,0% to 100% (3:1) EtOAc-EtOH in heptane) provided additional2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide. ¹H NMR(400 MHz, DMSO-d₆) δ 8.01-8.17 (m, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.75 (s,1H), 7.43-7.55 (m, 3H), 7.23-7.34 (m, 2H), 7.10 (d, J=2.5 Hz, 1H), 6.73(s, 2H), 3.93 (s, 3H). m/z (ESI, +ve) 345.0 (M+H)⁺.

Step 2:2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide

To a solution of2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzamide (2.11 g,6.12 mmol) in tetrahydrofuran (41 mL) was added Lawesson's reagent (1.49mL, 3.67 mmol), and the resulting mixture was stirred at rt for 1 h. Thereaction mixture was then diluted with EtOAc (60 mL) and sequentiallywashed with 2 M HCl (60 mL), saturated aqueous NaHCO₃ (60 mL), and brine(60 mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was sonicated in DCM (5 mL), and theresulting precipitate was collected by filtration, washed with DCM, anddried in vacuo provide2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide.Chromatographic purification of the filtrate (silica gel, 0% to 100%(3:1) EtOAc-EtOH in heptane) gave additional2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide:m/z (ESI, +ve) 361.0 (M+H)⁺.

Step 3:5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine

Hydrogen peroxide solution (30% in water, 2.2 mL, 21.3 mmol) was slowlyadded to an ice-cooled solution of2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzothioamide(1.92 g, 5.33 mmol) in pyridine (18 mL). The resulting mixture wasallowed to warm to rt and stir at rt for 18 h. The reaction mixture wasthen diluted with water (60 mL), and the resulting precipitate wascollected by filtration, sequentially washed with water and MeOH, anddried in vacuo to give5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine:¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 2H), 7.99-8.03 (m, 1H), 7.93 (d,J=8.3 Hz, 1H), 7.48-7.55 (m, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.31 (d, J=3.9Hz, 2H), 7.16 (d, J=2.5 Hz, 1H), 3.94 (s, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −124.71 (s, 1F). m/z (ESI, +ve) 359.0 (M+H)⁺.

Step 4:3,5-Dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole

5-Chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine(1.55 g, 4.31 mmol) was added portion-wise over 15 min to a suspensionof copper (II) chloride (0.870 g, 6.47 mmol) and tert-butyl nitrite(0.77 mL, 6.47 mmol) in acetonitrile (43 mL) at 65° C. The resultingmixture was stirred at 65° C. for 30 min and then cooled to ambienttemperature and diluted with ice water (50 mL). The precipitated solidwas collected by filtration, washed with water, and dried in vacuo. Theresidue was sonicated in DCM (10 mL), and the suspended solid wascollected by filtration, washed with DCM, and dried in vacuo to recoverunreacted5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-amine.The filtrate was concentrated in vacuo to give3,5-dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole.¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.96 (d, J=8.2 Hz, 1H),7.49-7.56 (m, 2H), 7.28-7.36 (m, 2H), 7.24-7.28 (m, 1H), 3.95 (s, 3H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −122.17 (s, 1F). m/z (ESI, +ve) 378.0(M+H)⁺.

Step 5: tert-Butyl(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate

A mixture of3,5-dichloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazole(100 mg, 0.264 mmol), DIPEA (0.14 mL, 0.793 mmol), and3-Boc-3-methylaminoazatidine (0.098 mL, 0.529 mmol, Beta PharmaScientific, Inc.) in DMF (1.3 mL) was stirred at rt for 18 h. Ice water(3 mL) was then added, and the resulting mixture was stirred for 15 min.The precipitated solid was then collected by filtration, washed withwater, and dried in vacuo to furnish tert-butyl(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate:m/z (ESI, +ve) 528.0 (M+H)⁺.

Step 6:N-(1-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-azetidinyl)-N-methyl-2-propenamide

The title compound was prepared from tert-butyl(1-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)azetidin-3-yl)(methyl)carbamate(131.1 mg, 0.248 mmol) in three steps following the procedure reportedin Method 1, Step 8: ¹H NMR (400 MHz, DMSO-d₆) δ 9.89-10.10 (m, 1H),7.79 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.43 (ddd, J=8.2, 5.1, 2.9 Hz,1H), 7.20-7.30 (m, 3H), 7.05 (d, J=2.2 Hz, 1H), 6.81 (dd, J=16.7, 10.5Hz, 1H), 6.10-6.23 (m, 1H), 5.69-5.81 (m, 1H), 5.37-5.59 (m, 1H),4.63-4.74 (m, 3H), 4.53-4.61 (m, 1H), 3.14-3.23 (m, 3H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −124.10 (s, 1F). m/z (ESI, +ve) 468.0 (M+H)⁺.

TABLE 5 Compounds 5-2 to 5-9 were prepared following the proceduredescribed in Method 5, Steps 1-6, above as follows: Ex.# ChemicalStructure Name Reagent 5-2

N-(1-(5-chloro-7-fluoro- 6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-3- methyl-3-azetidinyl)-2- propenamide Step 5:3-(Boc-amino)- 3-methylazetidine hydrochloride (Advanced ChemBlocks,Inc., Burlingame, CA, USA) 5-3

N-(1-(5-chloro-7-fluoro 6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-3- (hydroxymethyl)-3- azetidinyl)-2-propenamide Step5: tert-butyl 3- (hydroxymethyl)aze- tidin-3-ylcarbamate (OakwoodProducts, Inc. Estill, SC, USA) 5-4

1-((2S)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-2- methyl-1-piperazinyl)- 2-propen-1-one Step 5:(S)-1-N-boc- 2-methylpiperazine (Combi-blocks Inc., San Diego, CA, USA)5-5

1-((1R,5R)-6-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-2,6- diazabicyclo[3.2.0]heptan- 2-yl)-2-propen-1-oneStep 5: tert-butyl 2,6- diazabicyclo[3.2.0]hep- tane-2-carboxylate(eNovation Chemicals LLC, Bridgewater, NJ, USA) 5-6

1-((1S,5S)-6-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-2,6- diazabicyclo[3.2.0]heptan- 2-yl)-2-propen-1-oneStep 5: tert-butyl 2,6- diazabicyclo[3.2.0]hep- tane-2-carboxylate(eNovation Chemicals LLC, Bridgewater, NJ, USA) 5-7

1-((2R)-4-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-2- methyl-1-piperazinyl)- 2-propen-1-one Step 5:(R)-1-boc-2- methyl-piperazine (J&W Pharmlab, LLC, Levittown, PA, USA)5-8

1-(cis-2-(5-chloro-7- fluoro-6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-2,6- diazabicyclo[3.2.0]heptan- 6-yl)-2-propen-1-oneStep 5: 1-(2,6- diazabicyclo[3.2.0]hep- tan-6-yl)prop-2-en-1- one(eNovation Chemicals LLC, Bridgewater, NJ, USA)

5-9

1-(3-((5-chloro-7-fluoro-6- (3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3- yl)(methyl)amino)azetidin- 1-yl)prop-2-en-1-oneStep 5: 1- azetidinecarboxylic acid, 3- (methylamino)-, 1,1-dimethylethyl ester

Method 6 Example 6-1:1-(4-(6-(6-Amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D, 1.10 g, 2.45 mmol), bis(pinacolato)diboron (1.86 g,7.34 mmol), potassium acetate (0.61 mL, 9.8 mmol), and Pd(dppf)Cl₂-DCM(0.537 g, 0.734 mmol) in 1,4-dioxane (12 mL) was heated at 100° C. for40 h. The reaction mixture was then concentrated in vacuo andchromatographically purified (silica gel, 0% to 100% (3:1) EtOAc-EtOH inheptane) to provide tert-butyl4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate:¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 1H), 3.59 (br d, J=4.7 Hz, 4H),3.44-3.54 (m, 4H), 1.43 (s, 9H), 1.35 (s, 5H), 1.15 (s, 7H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −125.11 (s, 1F). m/z (ESI, +ve) 498.0 (M+H)⁺.

Step 2: tert-Butyl4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-chloro-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate(99.5 mg, 0.200 mmol), SPhos Pd G3 (17.3 mg, 0.020 mmol),6-bromo-5-chloropyridin-2-amine (Combi-blocks Inc., San Diego, Calif.,USA, 124 mg, 0.6 mmol), sodium carbonate (85 mg, 0.80 mmol) in water(0.25 mL), and 1,2-DCE (0.75 mL) was heated at 50° C. for 2 h. Thereaction mixture was concentrated in vacuo and chromatographicallypurified (silica gel, 0% to 100% (3:1) EtOAc-EtOH in heptane) to givetert-butyl4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate:m/z (ESI, +ve) 498.0 (M+H)⁺.

Step 3:1-(4-(6-(6-Amino-3-chloro-2-pyridinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

The title compound was prepared from tert-butyl4-(6-(6-amino-3-chloropyridin-2-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(31.6 mg, 0.063 mmol) in two steps following the procedure reported inMethod 1, Step 8: ¹H NMR (400 MHz, DMSO-d₆) δ 7.97-8.10 (m, 1H), 7.60(d, J=8.9 Hz, 1H), 6.86 (dd, J=16.6, 10.6 Hz, 1H), 6.57 (d, J=8.9 Hz,1H), 6.38 (s, 2H), 6.19 (dd, J=16.8, 2.3 Hz, 1H), 5.71-5.84 (m, 1H),3.86 (br d, J=19.9 Hz, 4H), 3.63 (br d, J=1.0 Hz, 4H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −126.04 (s, 1F). m/z (ESI, +ve) 452.0 (M+H)⁺.

TABLE 6 Compound 6-2 was prepared following the procedure described inMethod 6, Steps 1-3, above as follows: Ex.# Chemical Structure NameReagent 6-2

1-(4-(5-chloro-6-(3-chloro- 2-pyridinyl)-7-fluoro-2,1-benzothiazol-3-yl)-1- piperazinyl)-2-propen-1-one Step 2: 2-bromo-3-chloropyridine

Method 7 Example 7-1:1-((3R)-4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one|1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one

Step 1: 2-Amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoicacid

Prepared from Intermediate A using a procedure analogous to thatdescribed in Method 1, Step 7: m/z (ESI, +ve) 346.0 (M+H)⁺.

Step 2: tert-Butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate

A mixture of2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoic acid(0.150 g, 0.434 mmol), TBTU (0.188 g, 0.586 mmol), tert-butyl3-(difluoromethyl)piperazine-1-carboxylate (0.123 g, 0.521 mmol), andDIPEA (0.23 mL, 1.302 mmol) in DMF (4 mL) was stirred at ambienttemperature for 3 h. The reaction mixture was then washed with saturatedaqueous NaHCO₃, and the aqueous wash was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0-40% EtOAc/heptane) provided tert-butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate:m/z (ESI, +ve) 586 (M+Na)⁺.

Step 3: tert-Butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylate

Lawesson's reagent (0.041 mL, 0.10 mmol) was added to a solution oftert-butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)benzoyl)-3-(difluoromethyl)piperazine-1-carboxylate(0.095 g, 0.168 mmol) in THF (4 mL), and the resulting mixture wasstirred at 50° C. for 18 h. The reaction mixture was then concentratedin vacuo and purified by column chromatography (silica gel, 0-30%EtOAc/heptane) to give tert-butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylate:m/z (ESI, +ve) 602.2 (M+Na)⁺.

Step 4: tert-Butyl4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-3-(difluoromethyl)piperazine-1-carboxylate

NBS (0.022 g, 0.17 mmol) was added to a solution of tert-butyl4-(2-amino-5-chloro-3-fluoro-4-(3-methoxynaphthalen-1-yl)phenylcarbonothioyl)-3-(difluoromethyl)piperazine-1-carboxylatein THF (7 mL), and the resulting mixture was stirred at ambienttemperature for 15 min. The reaction mixture was diluted with water andwashed with 10% sodium thiosulfate. The aqueous wash was extracted withEtOAc, and the combined organic layers were then concentrated in vacuoto give tert-butyl4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)-3-(difluoromethyl)piperazine-1-carboxylate:m/z (ESI, +ve) 578.2 (M+H)⁺.

Step 5:1-((3R)-4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one|1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(difluoromethyl)-1-piperazinyl)-2-propen-1-one

Prepared using a procedure analogous to that described in Method 1, Step8: ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (br. s., 1H) 8.12 (d, J=2.2 Hz, 1H)7.80 (d, J=8.2 Hz, 1H) 7.43 (br t, J=7.0 Hz, 1H) 7.20-7.30 (m, 3H) 7.08(dd, J=5.8, 2.2 Hz, 1H) 6.78-6.91 (m, 1H) 6.27-6.70 (m, 1H) 6.20 (dd,J=16.6, 2.0 Hz, 1H) 5.76-5.84 (m, 1H) 4.73-4.87 (m, 1H) 4.19-4.72 (m,2H) 3.55-3.90 (m, 3H) 3.36-3.47 (m, 1H). m/z (ESI, +ve) 518.0 (M+H)⁺.

TABLE 7 Compounds 7-2 and 7-3 were prepared following the proceduredescribed in Method 7, Steps 1-5, above as follows: Ex.# ChemicalStructure Name Reagent 7-2

1-(4-(5-chloro-7- fluoro-6-(3-hydroxy- 1-naphthalenyl)-2,1-benzothiazol-3-yl)-3- (fluoromethyl)-1- piperazinyl)-2-propen- 1-oneStep 2: 3- fluoromethyl- piperazine-1- carboxylic acid tert-butyl ester(eNovation Chemicals LLC, Bridgewater, NJ, USA)

7-3

methyl 1-(5-chloro-7- fluoro-6-(3-hydroxy- 1-naphthalenyl)-2,1-benzothiazol-3-yl)-4- (2-propenoyl)-2- piperazinecarboxylate Step 2:4-boc- piperazine-2- carboxylic acid methyl ester (Combi-blocks Inc.,San Diego, CA, USA)

Method 8 Example 8-1:6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone

Step 1: 4-Bromo-5-chloro-2-fluorobenzamide

A mixture of 4-bromo-5-chloro-2-fluorobenzoic acid (23.3 g, 92 mmol) inthionyl chloride (67 mL, 0.92 mol) was stirred at 70° C. under a refluxcondenser for 1 h. The reaction mixture was then concentrated in vacuo,and the residue was taken up in 1,4-dioxane (200 mL), treated withammonium hydroxide (30% aqueous, 82 mL, 0.64 mol), and stirred at rt for15 min. The reaction mixture was concentrated in vacuo to give4-bromo-5-chloro-2-fluorobenzamide: m/z (ESI, +ve) 251.8 (M+H)⁺.

Step 2:4-Bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide

A mixture of 4-bromo-5-chloro-2-fluorobenzamide (5.90 g, 23.4 mmol) andoxalyl chloride (1 M in DCM; 12.9 mL, 25.7 mmol) in DCE (100 mL) wasstirred under a reflux condenser at 80° C. for 1 h. The reaction mixturewas then cooled to rt and 2-isopropylaniline (6.62 mL, 46.7 mmol) wasadded. The resulting mixture was stirred at rt for 15 min, then cooledto 0° C. The precipitated solid was removed by filtration, and thecollected filtrate was concentrated in vacuo to give4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide: ¹HNMR (400 MHz, DMSO-d₆) δ 11.06 (br. s., 1H) 10.31 (s, 1H) 7.97-8.05 (m,2H) 7.82 (d, J=7.2 Hz, 1H) 7.32-7.38 (m, 1H) 7.14-7.25 (m, 2H) 3.11(spt, J=6.8 Hz, 1H) 1.24 (d, J=6.8 Hz, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−113.6 (s, 1F). m/z (ESI, +ve) 412.7 and 414.6 (M+H)⁺.

Step 3:7-Bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione(Intermediate F)

KHMDS (1 M in THF, 8.30 mL, 8.30 mmol) was added to a mixture of4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl)carbamoyl)benzamide(1.56 g, 3.77 mmol) in THF (19 mL) at −20° C., and the resulting mixturewas allowed to warm to rt over 1 h. The reaction mixture was thendiluted with EtOAc (150 mL) and washed with saturated aqueous ammoniumchloride (2×100 mL). The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was suspended in DCM (5 mL),sonicated, collected by filtration, and dried in vacuo to give7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione: ¹HNMR (400 MHz, CDCl₃) δ 9.43 (br. s., 1H) 8.29 (s, 1H) 7.55-7.59 (m, 2H)7.39-7.44 (m, 1H) 7.16 (d, J=7.8 Hz, 1H) 6.75 (s, 1H) 2.59-2.77 (m, 1H)1.17-1.24 (m, 3H) 1.11 (d, J=6.8 Hz, 3H). m/z (ESI, +ve) 392.9 and 395.0(M+H)⁺.

Step 4:6-Chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione

A mixture of7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione(Intermediate F, 1.17 g, 2.96 mmol), (2-fluoro-6-methoxyphenyl)boronicacid (2.02 g, 11.9 mmol), SPhos Pd G3 (0.128 g, 0.148 mmol), andpotassium carbonate (2 M in water, 4.45 mL, 8.90 mmol) in DME (30 mL)was stirred at 85° C. for 16 h. The reaction mixture was then dilutedwith EtOAc (150 mL) and washed with saturated aqueous NaHCO₃ (3×100 mL).The organic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. Chromatographic purification of the residue (silica gel, 0-50%EtOAc in heptane) gave6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione:¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (d, J=1.2 Hz, 1H) 8.11 (d, J=3.3 Hz,1H) 7.53-7.59 (m, 1H) 7.48 (tt, J=7.0, 2.2 Hz, 1H) 7.38-7.44 (m, 1H)7.32-7.37 (m, 2H) 6.93 (dd, J=8.4, 4.3 Hz, 1H) 6.86 (t, J=8.7 Hz, 1H)6.15 (s, 1H) 3.66 (d, J=30 Hz, 3H) 2.73 (dq, J=14.2, 7.0 Hz, 1H) 1.11(t, J=7.1 Hz, 3H) 1.03 (dd, J=12.7, 6.8 Hz, 3H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −113.8 (s, 1F) −115.2 (s, 1F). m/z (ESI, +ve) 439.1 (M+H)⁺.

Step 5:4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one

To a solution of6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione(0.395 g, 0.900 mmol) and Et₃N (0.753 mL, 5.40 mmol) in acetonitrile (9mL) was added phosphorus oxychloride (0.503 mL, 5.40 mmol), and theresulting solution was stirred at 80° C. for 1.5 h. The reaction mixturewas concentrated in vacuo to give4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one:m/z (ESI, +ve) 457.1 (M+H)⁺.

Alternative procedure for Step 5 (used as noted in the table below): Toa stirred mixture of the product from Step 4 (1.0 equiv.), triethylamine(18.0 equiv.), and 1H-benzo[d][1,2,3]triazole (12 equiv.) inacetonitrile (0.07 M) was added phosphorus oxychloride (6.0 equiv.), andthe resulting reaction mixture was stirred at 80° C. for 3.5 h. Thereaction mixture was then poured slowly into rapidly stirred water (100mL) at 10° C. The aqueous suspension was stirred for 15 min before beingextracted with EtOAc (100 mL). The organic layer was washed with brine(100 mL), dried over MgSO₄, filtered, and concentrated in vacuo to givea benzotriazole adduct intermediate that was used directly in Step 6.

Step 6: tert-Butyl4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate

A solution of4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one(obtained from Method 8, Step 5), tert-butyl piperazine-1-carboxylate(0.335 g, 1.80 mmol), and Et₃N (0.753 mL, 5.40 mmol) in DCE (9 mL) wasstirred at 60° C. for 20 min. The reaction mixture was diluted withEtOAc (100 mL) and washed with saturated aqueous NaHCO₃ (3×75 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-60% (3:1)EtOAc-EtOH in heptane) provided tert-butyl4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate:m/z (ESI, +ve) 607.3 (M+H)⁺.

Note:

When (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one2,2,2-trifluoroacetate was used, it was synthesized as follows:

(S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one 2,2,2-trifluoroacetate

Step 6-a: (S)-tert-Butyl 4-acryloyl-2-methylpiperazine-1-carboxylate

Acryloyl chloride (1.34 mL, 16.5 mmol) was added to a solution of(S)-1-boc-2-methyl-piperazine (3.00 g, 15.0 mmol, Boc Sciences, Shirley,N.Y.) in THF (30.0 mL) at −10° C., and the resulting mixture was stirredat −10° C. for 5 min. Triethylamine (6.26 mL, 44.9 mmol) was then slowlyadded, and the resulting mixture was stirred at −10° C. for 15 min, thenallowed to warm to rt. The reaction mixture was partitioned betweenEtOAc and saturated aqueous NaHCO₃. The aqueous layer was extracted withEtOAc (3×), and the organic layers were then combined, dried over MgSO₄,filtered, and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0-100% EtOAc in heptane) furnished (S)-tert-butyl4-acryloyl-2-methylpiperazine-1-carboxylate: ¹H NMR (400 MHz, DMSO-d₆) δ6.72-6.85 (m, 1H) 6.10-6.18 (m, 1H) 5.68-5.76 (m, 1H) 4.08-4.32 (m, 2H)3.68-4.03 (m, 2H) 2.86-3.14 (m, 2H) 2.66-2.80 (m, 1H) 1.38-1.43 (s, 9H)0.96-1.04 (m, 3H). m/z (ESI, +ve) 277.3 (M+Na)⁺.

Step 6-b: (S)-1-(3-Methylpiperazin-1-yl)prop-2-en-1-one2,2,2-trifluoroacetate

A mixture of (S)-tert-butyl 4-acryloyl-2-methylpiperazine-1-carboxylate(3.21 g, 12.62 mmol) and TFA (4.7 mL, 63.1 mmol) in DCM (16 mL) wasstirred at rt for 24 h. The reaction mixture was then concentrated invacuo to give (S)-1-(3-methylpiperazin-1-yl)prop-2-en-1-one2,2,2-trifluoroacetate: ¹H NMR (400 MHz, DMSO-d₆) δ 8.70-8.99 (m, 1H)6.74-6.91 (m, 1H) 6.12-6.26 (m, 1H) 5.70-5.84 (m, 1H) 4.25-4.44 (m, 1H)4.07-4.25 (m, 1H) 3.49-3.53 (m, 1H) 3.22-3.32 (m, 2H) 2.92-3.08 (m, 2H)1.14-1.29 (m, 3H). m/z (ESI, +ve) 155.1 (M+H)⁺.

Step 7:6-Chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-one

A solution of tert-butyl4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate(0.594 g, 0.978 mmol) in TFA (4 mL) was stirred at ambient temperaturefor 30 min. The reaction mixture was concentrated in vacuo to give6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-one:m/z (ESI, +ve) 507.2 (M+H)⁺.

Step 8:4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one

To an ice-cooled solution of6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)-4-(piperazin-1-yl)quinazolin-2(1H)-oneand DIPEA (0.85 mL, 4.9 mmol) in DCM (10 mL) at 0° C. was added acryloylchloride (0.079 mL, 0.98 mmol), and the resulting mixture was stirred at0° C. for 30 min. The reaction mixture was then diluted with EtOAc (100mL) and washed with saturated aqueous NaHCO₃ (3×75 mL). The organiclayer was dried over Na₂SO₄, decanted, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0-100% (3:1)EtOAc-EtOH in heptane) gave4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one:¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=1.2 Hz, 1H) 7.41-7.54 (m, 2H)7.29-7.37 (m, 2H) 7.14 (dt, J=7.8, 1.7 Hz, 1H) 6.70-6.79 (m, 2H)6.58-6.68 (m, 1H) 6.50 (d, J=7.4 Hz, 1H) 6.39 (dd, J=16.8, 1.8 Hz, 1H)5.75-5.84 (m, 1H) 3.79-4.06 (m, 8H) 3.75 (s, 2H) 3.66 (s, 1H) 2.69 (tt,J=13.4, 6.8 Hz, 1H) 1.20-1.24 (m, 3H) 1.07 (dd, J=6.8, 3.9 Hz, 3H). ¹⁹FNMR (377 MHz, CDCl₃) δ −113.05 (s, 1F) −113.55 (s, 1F). m/z (ESI, +ve)561.2 (M+H)⁺.

Step 9:6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone

BBr₃ (1 M in DCE, 3.3 mL, 3.3 mmol) was added to an ice-cooled solutionof4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one(0.372 g, 0.663 mmol) in DCE (1.7 mL), and the resulting mixture wasstirred at 0° C. for 20 min, then allowed to warm to rt and stir at rtfor 2 h. Saturated aqueous NaHCO₃ was added to the reaction mixture,followed by EtOAc (150 mL). The organic layer was separated and washedwith saturated aqueous NaHCO₃ (3×100 mL). The organic layer was thendried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0-100% (3:1) EtOAc-EtOH inheptane) provided6-chloro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone:¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (br. d., J=15.1 Hz, 1H) 8.03 (d, J=1.2Hz, 1H) 7.51-7.56 (m, 1H) 7.45 (t, J=7.6 Hz, 1H) 7.33 (tdd, J=7.5, 7.5,3.8, 1.4 Hz, 1H) 7.14-7.25 (m, 2H) 6.84 (dd, J=16.8, 10.4 Hz, 1H)6.62-6.74 (m, 2H) 6.14-6.26 (m, 2H) 5.71-5.78 (m, 1H) 3.71-3.99 (m, 8H)2.52-2.59 (m, 1H) 1.02-1.12 (m, 6H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −113.6(s, 1F) −114.8 (s, 1F). m/z (ESI, +ve) 547.1 (M+H)⁺.

TABLE 8 Compounds 8-2 to 8-6 were prepared following the proceduredescribed in Method 8, Steps 1-9, above as follows: Method Starting Ex.#Chemical Structure Name changes material Reagents 8-2

6-chloro-7-(2- fluoro-6- hydroxyphenyl)- 1-(2-(2- propanyl)phen-yl)-4-(4-(2- propenoyl)-1- piperazinyl)pyr- ido[2,3-d]pyrim-idin-2(1H)-one Omit steps 7 and 8 2,5,6- trichloro- nicotinic acid Step4: sodium carbonate Step 6: 1-(piperazin-1- yl)prop-2-en-1- one(eNovation Chemicals LLC, Bridgewater, NJ, USA) 8-3

6-chloro-7-(2- fluoro-6- hydroxyphenyl)- 4-((2S)-2- methyl-4-(2-propenoyl)-1- piperazinyl)-1- (2-(2- propanyl)phen- yl)-2(1H-quinazolinone — 4-bromo- 5-chloro- 2-fluoro- benzoic acid Step 6: (S)-tert-butyl 3- methylpiper- azine-1- carboxylate (CNH Technologies, Inc.,Woburn, MA) 8-4

6-chloro-1-(2,6- diethylphenyl)- 7-(2-fluoro-6- hydroxyphenyl)-4-((2S)-2- methyl-4-(2- propenoyl)-1- piperazinyl)pyr- ido[2,3-d]pyr-imidin-2(1H)- one Omit steps 7 and 8 2,5,6- trichloro- nicotinic acidStep 2: 2,6- diethylaniline, Step 5: benzotriazole, Step 6: (S)-1-(3-methylpiperazin- 1-yl)prop-2-en- 1-one 2,2,2- trifluoroacetate (See Step6 note for synthesis) 8-5

6-chloro-1-(4- cyclopropyl-3- pyridinyl)-7-(2- fluoro-6- hydroxyphenyl)-4-(4-(2- propenoyl)-1- piperazinyl)- 2(1H)- quinazolinone — 4-bromo-5-chloro- 2-fluoro- benzoic acid Step 2: 4-cyclo- propylpyridin- 3-amine(Combi-Phos Catalysts Inc. Trenton, NJ, USA), 1,4- dioxane/water, 100°C. 8-6

6-chloro-7-(2- fluoro-6- hydroxyphenyl)- 4-((2S)-2- methyl-4-(2-propenoyl)-1- piperazinyl)-1- (2-(2- propanyl)phen- yl)pyrido[2,3-d]pyrimidin- 2(1H)-one Omit steps 7 and 8 2,5,6- trichloro- nicotinicacid Step 4: sodium carbonate Step 6: (S)-1-(3- methylpiperazin-1-yl)prop-2-en- 1-one 2,2,2- trifluoroacetate (See Step 6 note forsynthesis)

Method 9 Example 9-1:6-Chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone

Step 1: 7-Bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one

To a mixture of7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione(Intermediate F, 470 mg, 1.194 mmol) and DIPEA (0.623 mL, 3.58 mmol) inacetonitrile (11.4 mL) was added phosphorus oxychloride (0.915 mL, 5.97mmol). The resulting mixture was heated at 80° C. for 2 h, then cooledto ambient temperature and concentrated in vacuo to give7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one: m/z(ESI, +ve) 413.0 (M+H)⁺.

Step 2:(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one

A mixture of7-bromo-4,6-dichloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one (492 mg,1.19 mmol), (S)-4-N-boc-2-methyl piperazine (478 mg, 2.39 mmol), andDIPEA (0.623 mL, 3.58 mmol) in DMF (2.3 mL) was stirred at rt for 10min. Ice water (10 mL) was then added, and the resulting mixture stirredfor 15 min. The precipitated solid was collected by filtration, washedwith water, and dried in vacuo to give (S)-tert-butyl4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate:m/z (ESI, +ve) 577.1 (M+H)⁺.

TFA (2.0 mL, 26.8 mmol) was added to a solution of (S)-tert-butyl4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate(297 mg, 0.516 mmol) in DCM (2.0 mL), and the resulting mixture wasstirred at rt for 15 min. Concentration of the resulting mixture invacuo provided(S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quinazolin-2(1H)-one:m/z (ESI, +ve) 477.0 (M+H)⁺.

Acryloyl chloride (0.258 M in DCM, 4.0 mL, 1.031 mmol) was added to anice-cooled mixture of(S)-7-bromo-6-chloro-1-(2-isopropylphenyl)-4-(2-methylpiperazin-1-yl)quinazolin-2(1H)-oneand DIPEA (0.269 mL, 1.547 mmol) in DCM (2.0 mL), and the resultingmixture was stirred at 0° C. for 20 min. Concentration in vacuo followedby chromatographic purification of the residue (silica gel, 0-100% (3:1)EtOAc-EtOH in heptane) gave(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one:¹H NMR (400 MHz, DMSO-d₆) δ 7.91-8.08 (m, 1H), 7.49-7.67 (m, 2H), 7.41(br d, J=5.8 Hz, 1H), 7.21 (br s, 1H), 6.76-6.98 (m, 1H), 6.52-6.67 (m,1H), 6.09-6.29 (m, 1H), 5.75 (br s, 1H), 4.61-4.96 (m, 1H), 4.23-4.48(m, 1H), 3.93-4.21 (m, 2H), 3.50-3.77 (m, 1H), 3.33-3.49 (m, 1H),3.23-3.28 (m, 1H), 2.94-3.24 (m, 1H), 1.27 (br d, J=9.3 Hz, 6H), 1.09(br s, 3H). m/z (ESI, +ve) 531.1 (M+H)⁺.

Step 3:(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one

A mixture of(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one(120 mg, 0.226 mmol),2-(2,3-dichloro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(82 mg, 0.272 mmol), Na₂CO₃ (96 mg, 0.906 mmol), and Pd(PPh₃)₄ (26.2 mg,0.023 mmol) in 1,4-dioxane (1.6 mL) and water (0.4 mL) was heated at 90°C. for 17 h. The reaction mixture was then concentrated in vacuo andchromatographically purified (silica gel, 0-100% (3:1) EtOAc-EtOH inheptane) to provide(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one:m/z (ESI, +ve) 627.0 (M+H)⁺.

Step 4:6-Chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone

BBr₃ (1 M in hexanes, 0.32 mL, 0.320 mmol) was added to an ice-cooledmixture of(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-7-(2,3-dichloro-5-methoxyphenyl)-1-(2-isopropylphenyl)quinazolin-2(1H)-one(40 mg, 0.064 mmol) and DCE (1.0 mL), and the resulting mixture wasstirred at 0° C. for 30 min. Saturated aqueous NaHCO₃ (2.0 mL) wasadded, and the resulting mixture was extracted with (2:1) DCM/MeOH (5mL). The organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0-10% MeOH in DCM) gave6-chloro-7-(2,3-dichloro-5-hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)-1-(2-(2-propanyl)phenyl)-2(1H)-quinazolinone:¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (br d, J=17.0 Hz, 1H), 7.86-8.11 (m,1H), 7.50-7.63 (m, 1H), 7.47 (br t, J=6.0 Hz, 1H), 7.36 (t, J=7.5 Hz,1H), 7.15-7.26 (m, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.78-6.96 (m, 1H),6.44-6.58 (m, 1H), 6.11-6.29 (m, 2H), 5.71-5.82 (m, 1H), 4.68-4.98 (m,1H), 3.96-4.52 (m, 3H), 3.52-3.85 (m, 2H), 3.34-3.51 (m, 1H), 2.95-3.26(m, 1H), 1.27-1.41 (m, 3H), 0.95-1.13 (m, 6H). m/z (ESI, +ve) 611.0(M+H)⁺.

TABLE 9 Compounds 9-2 to 9-14 were prepared following the proceduredescribed in Method 9, Steps 1-4, above as follows: Ex.# ChemicalStructure Name Method changes Starting material Reagent 9-2

7-bromo-6-chloro- 4-((2S)-2-methyl-4- (2-propenoyl)-1-piperazinyl)-1-(2-(2- propanyl)phenyl)- 2(1H)-quinazolinone Omit Steps 3and 4 7-bromo-6-chloro- 1-(2-isopropylphen- yl)quinazoline-2,4(1H,3H)-dione — 9-3

7-(5-amino-2- chlorophenyl)-6- chloro-4-((2S)-2- methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2- (2-propanyl)phenyl)-2(1H)-quinazolinone Omit Step 4 7-bromo-6-chloro- 1-(2-isopropylphen-yl)quinazoline- 2,4(1H,3H)-dione Step 3: (5- amino-2-chloro-phenyl)boronic acid hydrochloride (Combi-blocks Inc., San Diego, CA,USA) 9-4

1-(2-(2- butanyl)phenyl)-6- chloro-7-(3- hydroxy-1- naphthalenyl)-4-(4-(2-propenoyl)-1- piperazinyl)-2(1H)- quinazolinone SM prepared accordingto Method 8, steps 1-3 7-bromo-1-(2-(sec- butyl)phenyl)-6-chloroquinazoline- 2,4(1H,3H)-dione Method 8, Step 2: (2-sec- butylphen-yl)amine (Key Organics Inc., Bedford, MA, USA), Step 2:1-boc-piperazine, Step 3: (3- methoxynaph- thalen-1- yl)boronic acid(Ark Pharm Inc. Arlington Heights, IL, USA), SPhos Pd G3, K₂CO₃,1,4-dioxane/ water, 100° C.

9-5

3-(6-chloro-7-(2- fluoro-6- hydroxyphenyl)- 2-oxo-4-(4-(2- propenoyl)-1-piperazinyl)-1(2H)- quinazolinyl) benzonitrile SM prepared according toMethod 8, steps 1-3 3-(7-bromo- 6-chloro-2,4- dioxo-3,4-dihydroquinazolin- 1(2H)- yl)benzonitrile Method 8, Step 2: 3-amino-benzonitrile (Frontier Scientific Services, Inc., Newark, DE, USA), Step2: 1-boc-piperazine, Step 3: 2-fluoro- 6-hydroxyphenyl boronic acid(Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3, K₂CO₃, 1,4-dioxane/water, 100° C. 9-6

6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2- fluoro-6-hydroxyphenyl)-4- (4-(2-propenoyl)-1- piperazinyl)-2(1H)- quinazolinoneSM prepared according to Method 8, steps 1-3 7-bromo-6-chloro- 1-(3-cyclopropylpyridin- 4-yl)quinazoline- 2,4(1H,3H)-dione Method 8, Step 2:3- cyclopropyl- pyridin-4-amine (Combi-Phos Catalysts Inc. Trenton, NJ,USA), Step 2: 1- boc-piperazine, Step 3: 2-fluoro- 6-hydroxyphenylboronic acid (Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3,K₂CO₃, 1,4- dioxane/water, 100° C. 9-7-2

6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2- fluoro-6-hydroxyphenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1- piperazinyl)-2(1H)-quinazolinone [2^(nd) eluting isomer] SM prepared according to Method 8,steps 1-3 7-bromo-6-chloro- 1-(3- cyclopropylpyridin- 4-yl)quinazoline-2,4(1H,3H)-dione Method 8, Step 2: 3- cyclopropyl- pyridin-4-amine(Combi-Phos Catalysts Inc. Trenton, NJ, USA), Step 3: 2-fluoro-6-hydroxyphenyl boronic acid (Combi-blocks Inc., San Diego, CA, USA),SPhos Pd G3, K₂CO₃, 1,4- dioxane/water, 100° C. 9-7-1

6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(2- fluoro-6-hydroxyphenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1- piperazinyl)-2(1H)-quinazolinone [1^(st) eluting isomer] SM prepared according to Method 8,steps 1-3 7-bromo-6-chloro- 1-(3- cyclopropylpyridin- 4-yl)quinazoline-2,4(1H,3H)-dione Method 8, Step 2: 3- cyclopropyl- pyridin-4-amine(Combi-Phos Catalysts Inc. Trenton, NJ, USA), Step 3: 2-fluoro-6-hydroxyphenyl boronic acid (Combi-blocks Inc., San Diego, CA, USA),SPhos Pd G3, K₂CO₃, 1,4- dioxane/water, 100° C. 9-9

6-chloro-1-(3- cyclopropyl-4- pyridinyl)-7-(5- methyl-1H-indazol-4-yl)-4-((2S)-2- methyl-4-(2- propenoyl)-1- piperazinyl)-2(1H)-quinazolinone SM prepared according to Method 8, steps 1-3, omit step 47-bromo-6-chloro- 1-(3- cyclopropylpyridin- 4-yl)quinazoline-2,4(1H,3H)-dione Method 8, Step 2: 3- cyclopropyl- pyridin-4-amine,(Combi-Phos Catalysts Inc. Trenton, NJ, USA), Step 3: 4-borono-5-methyl-1h- indazole (Ark- Pharm Inc.), SPhos Pd G3, K₂CO₃, 1,4-dioxane/water, 100° C. 9-10

6-chloro-7-(2,3- dichlorophenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-piperazinyl)-1-(2- (2-propanyl)phenyl)- 2(1H)-quinazolinone Omit Step 47-bromo-6-chloro- 1-(2-isopropylphen- yl)quinazoline- 2,4(1H,3H)-dioneStep 3: 2,3- dichlorobenzene- boronic acid (Alfa Aesar, Haver Hill, MA,USA) 9-11

6-chloro-7-(2- chlorophenyl)-4- ((2S)-2-methyl-4- (2-propenoyl)-1-piperazinyl)-1-(2- (2-propanyl)phenyl)- 2(1H)-quinazolinone Omit Step 47-bromo-6-chloro- 1-(2-isopropylphen- yl)quinazoline- 2,4(1H,3H)-dioneStep 3: 2- chlorobenzene- boronic acid (Alfa Aesar, Haver Hill, MA, USA)9-12

7-(1H-benzotriazol- 1-yl)-6-chloro-1- (2,6-diethylphenyl)-4-((2S)-2-methyl-4- (2-propenoyl)-1- piperazin- yl)pyrido[2,3-d]pyrimidin-2(1H)- one SM prepared according to Method 8, steps 1-3.Omit steps 2-2 and 2-3; compound isolated in step 2-1 2,5,6-trichloronicotinic acid Method 8 Step 2: 2,6- diethylaniline. Step 1:benzotri- azole(see Method 8, step 5 alternate conditions), Step 2-1:(S)-1- (3- methylpiperazin- 1-yl)prop-2- en-1-one 2,2,2-trifluoroacetate (See Method 8 Step 6 note for synthesis) 9-13

6-chloro-7-(3- hydroxy-1- naphthalenyl)-1- (2-(2- propanyl)phenyl)-4-(4-(2- propenoyl)-1- piperazinyl)-2(1H)- quinazolinone —7-bromo-6-chloro- 1-(2-isopropyl- phenyl)quinazoline- 2,4(1H,3H)-dioneStep 1: benzo- triazole(see Method 8, step 5 alternate conditions), Step2-1: tert-butyl piperazine-1- carboxylate Step 2-3: NEt₃ Step 3: SPhosPd G3, (3- methoxynaph- thalen-1- yl)boronic acid, DME 9-14

6-chloro-1-((1R)- 2,2- dimethylcyclohexyl)- 7-(2-fluoro-6-hydroxyphenyl)-4- (4-(2-propenoyl)-1- piperazinyl)py-rido[2,3-d]pyrimidin- 2(1H)-one|6- chloro-1-((1S)-2,2-dimethylcyclohexyl)- 7-(2-fluoro-6- hydroxyphenyl)-4-(4-(2-propenoyl)-1- piperazinyl)pyrido[ 2,3-d]pyrimidin- 2(1H)-one SMprepared according to Method 8, steps 1-3 Omit steps 2-2, 2-3, and 42,5,6- trichloronicotinic acid Method 8 Step 2: 2,2- dimethylcyclo-hexan-1-amine Step 2(1): 1- (piperazin-1- yl)prop-2-en-1- one (eNovationChemicals LLC, Bridgewater, NJ, USA) Step 3: SPhos Pd G3, 2-fluoro-6-hydroxyphenyl boronic acid Combi-blocks Inc., San Diego, CA, USA), DME

Method 10 Example 10-1:1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-methylphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: 6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G)

Hydrazine (0.232 mL, 10.1 mmol) was added to a mixture of5,6-dichloroisobenzofuran-1,3-dione (2.00 g, 9.22 mmol, TCI America,Portland, Oreg., USA) and ethanol (30 mL), and the resulting mixture washeated at reflux for 2 h before being cooled to rt. The resultingprecipitate was collected by filtration and washed with water to give6,7-dichloro-2,3-dihydrophthalazine-1,4-dione: m/z (ESI, +ve) 231.1(M+H)⁺.

Step 2:6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione

A mixture of 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (IntermediateG, 3.80 g, 16.45 mmol), 2-fluoro-6-hydroxyphenylboronic acid (10.26 g,65.8 mmol, Combi-blocks Inc., San Diego, Calif., USA), SPhos Pd G3(1.423 g, 1.645 mmol), and 2M aqueous Na₂CO₃ (32.9 mL, 65.8 mmol) in DME(60 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooledto rt and diluted with water (200 mL) and EtOAc (300 mL). The aqueouslayer was separated, acidified with 5 N HCl, and extracted with EtOAc(300 mL). The combined organic layers were washed with brine (200 mL),dried over MgSO₄, filtered, and concentrated in vacuo. The residue wassuspended in DCM (50 mL) and collected by filtration to give6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione:m/z (ESI, +ve) 307.0 (M+H)⁺.

Step 3:6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione

tert-Butyl(chloro)diphenylsilane (2.67 mL, 10.25 mmol) was added to anice-cooled mixture of6-chloro-7-(2-fluoro-6-hydroxyphenyl)-2,3-dihydrophthalazine-1,4-dione(2.62 g, 8.54 mmol) and TEA (4.75 mL, 34.2 mmol) in acetonitrile (40mL), and the resulting mixture was stirred at 0° C. for 15 min, thenwarmed to rt and stirred for 1.5 h. Additionaltert-butyl(chloro)diphenylsilane (2.67 mL, 10.25 mmol) was added, andthe resulting mixture was stirred at rt for 16 h. The reaction mixturewas subsequently diluted with water (300 mL), acidified with 5 N HCl,and extracted with EtOAc (300 mL). The organic layer was separated andsequentially washed with brine (250 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was taken up in DCM (200 mL), TFA (20mL) was added, and the resulting mixture was stirred at rt for 45 min.The reaction mixture was then diluted with saturated aqueous NaHCO₃ (200mL) and extracted with DCM (2×250 mL). The combined organic extractswere dried over MgSO₄, filtered, and concentrated in vacuo to give6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione:m/z (ESI, +ve) 545.2 (M+H)⁺.

Step 4:6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine

Pyridine (1.45 mL, 17.1 mmol) was added to a mixture of6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-2,3-dihydrophthalazine-1,4-dione(4.66 g, 8.55 mmol) and phosphorus oxychloride (6.39 mL, 68.4 mmol), andthe resulting mixture was heated at 100° C. for 1.5 h. The reactionmixture was then cooled to rt and slowly poured into stirred water (300mL) while maintaining an internal temperature of <10° C. After stirringfor 15 min, the resulting mixture was extracted with EtOAc (400 mL), andthe organic extract was sequentially washed with brine (250 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0-25% EtOAc in heptane)provided6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine:m/z (ESI, +ve) 581.1 (M+H)⁺.

Step 5: tert-Butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H)

1-Boc-piperazine (5.00 g, 26.9 mmol) was added to a mixture of6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-1,4,7-trichlorophthalazine(5.21 g, 8.95 mmol) and triethylamine (3.77 mL, 26.9 mmol) in DCM (35mL), and the resulting mixture was stirred at rt for 19 h. The reactionmixture was then partitioned between DCM (300 mL) and saturated aqueousNaHCO₃ (200 mL). The organic layer was separated, dried over MgSO₄,filtered, and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0-50% EtOAc in heptane) gave a mixture oftert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylateand tert-butyl4-(7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,6-dichlorophthalazin-1-yl)piperazine-1-carboxylate.The individual regioisomers were isolated by chiral SFC purification(OJ-H column (30×250 mm, 5 μm), 15% (20 mM NH₃ in MeOH) in supercriticalCO₂), providing tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalaazin-1-yl)piperazine-1-carboxylateas the second-eluting isomer: ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H)8.17 (s, 1H) 7.56-7.61 (m, 4H) 7.40-7.46 (m, 2H) 7.31-7.37 (m, 4H)6.99-7.07 (m, 1H) 6.77 (t, J=8.61 Hz, 1H) 6.42 (d, J=8.22 Hz, 1H)3.72-3.77 (m, 4H) 3.53-3.59 (m, 4H) 1.51 (s, 9H) 0.66 (s, 9H). m/z (ESI,+ve) 731.2 (M+H)⁺.

Step 6:6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine

Trifluoroacetic acid (2 mL, 26.8 mmol) was added to a stirred solutionof tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H, 1.21 g, 1.654 mmol) in DCM (10 mL), and the resultingmixture was stirred at rt for 1.5 h. The reaction mixture was thendiluted with saturated aqueous NaHCO₃ (75 mL) and extracted with DCM(2×100 mL). The combined organic extracts were dried over MgSO₄,filtered, and concentrated in vacuo to give6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine:m/z (ESI, +ve) 631.3 (M+H)⁺.

Step 7:1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

Acryloyl chloride (0.148 mL, 1.81 mmol) was added to a mixture of6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichloro-1-(piperazin-1-yl)phthalazine(1.04 g, 1.647 mmol) and triethylamine (0.694 mL, 4.94 mmol) in DCM (10mL), and the resulting mixture was stirred at rt for 45 min. Saturatedaqueous NaHCO₃ (75 mL) was added, and the resulting mixture wasextracted with DCM (3×100 mL). The combined organic extracts were driedover MgSO₄, filtered, and concentrated in vacuo to give1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one:m/z (ESI, +ve) 685.1 (M+H)⁺.

Step 8:1-(4-(4,7-Dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate I)

TBAF (1 M in THF, 3.3 mL, 3.30 mmol) was added to a solution of1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(1.13 g, 1.648 mmol) in THF (10 mL), and the resulting mixture wasstirred at rt for 15 min. The reaction mixture was concentrated invacuo, and the residue was purified by column chromatography (silicagel, 0-100% EtOAc in heptane) to give1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (br s, 1H) 8.31 (s, 1H) 8.14 (s, 1H)7.31-7.40 (m, 1H) 6.78-6.92 (m, 3H) 6.17 (dd, J=16.63, 2.35 Hz, 1H) 5.74(dd, J=10.37, 2.35 Hz, 1H) 3.79-3.92 (m, 4H) 3.46-3.55 (m, 4H). m/z(ESI, +ve) 447.0 (M+H)⁺.

Step 9:1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224mmol, Frontier Scientific Inc., Logan Utah, USA), Pd(PPh₃)₄ (6.46 mg,5.59 μmol, Strem Chemicals Inc., NewburyPort, Mass., USA), and 2Maqueous Na₂CO₃ (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) wasstirred at 40° C. for 18 h. The reaction mixture was then diluted withEtOAc (20 mL) and washed with water (15 mL). The organic layer wasseparated and sequentially washed with brine (15 mL), dried over MgSO₄,filtered, and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0-100% EtOAc in heptane) furnished1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one:¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (br s, 1H) 8.33 (s, 1H) 7.36-7.45 (m,2H) 7.24-7.36 (m, 4H) 6.90 (dd, J=16.63, 10.37 Hz, 1H) 6.70-6.80 (m, 2H)6.18 (dd, J=16.73, 2.25 Hz, 1H) 5.75 (dd, J=10.56, 2.15 Hz, 1H)3.83-3.97 (m, 4H) 3.47-3.62 (m, 4H) 1.98-2.06 (m, 3H). m/z (ESI, +ve)503.1 (M+H)⁺.

TABLE 10 Compounds 10-2 to 10-13 were prepared following the proceduredescribed in Method 10, Steps 1-9, above as follows: Method Ex.#Chemical Structure Name changes Reagent 10-2

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(2-methoxyphenyl)phthal- azin-1-yl)piperazin-1- yl)prop-2-en-1-one — Step9: 2- methoxybenzeneboronic acid 10-3

1-(4-(7-chloro-4-(5- chloro-2- methylphenyl)-6-(2- fluoro-6-hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step9: (5-chloro-2- methylphenyl)boronic acid (Combi-blocks Inc., San Diego,CA, USA) 10-4

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(2- (2-propanyl)phenyl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9: 2-isopropylphenylboronic acid (Alfa Aesar, Haver Hill, MA, USA) 10-5

1-(4-(7-chloro-4-(2- ethylphenyl)-6-(2- fluoro-6- hydroxyphenyl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9: 2-ethylbenzeneboronic acid (Alfa Aesar, Haver Hill, MA, USA) 10-6

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(4-methyl-3-pyridinyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one —Step 9: 4- methylpyridine-3- boronic acid pinacol ester (run at 60° C.)10-7

1-(4-(7-chloro-4-(2,6- dimethylphenyl)-6-(2- fluoro-6- hydroxyphenyl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9: 2,6-dimethylphenylboronic acid (run at 80° C.) 10-8

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(2-methyl-3-pyridinyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one —Step 9: 2- methylpyridine-3- boronic acid pinacol ester (FrontierScientific, Inc. Logan, UT, USA) 10-9

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4- (1H-indol-4-yl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9: 1H-indol-4-yl-4-boronic acid 10-10

1-(4-(7-chloro-4-(2- cyclopropylphenyl)-6- (2-fluoro-6-hydroxyphenyl)-1- phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step9: 2- cyclopropylbenzene- boronic acid (Combi- Phos Catalysts, Inc.,Trenton, NJ, USA) 10-11

1-(4-(7-chloro-4-(2- chlorophenyl)-6-(2- fluoro-6- hydroxyphenyl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9: 2-chlorophenylboronic acid (Matrix Scientific, Columbia, SC, USA) 10-12

1-(4-(7-chloro-6-(2- fluoro-6- hydroxyphenyl)-4-(5- methyl-1H-indazol-4-yl)-1-phthalazinyl)-1- piperazinyl)-2-propen- 1-one — Step 9:(5-methyl-1H- indazol-4-yl)boronic acid (Combi-Blocks, Inc., San Diego,CA, USA) 10-13

1-(4-(4,7-dichloro-6- (2-fluoro-6- hydroxyphenyl)-1- phthalazinyl)-1-piperazinyl)-2-propen- 1-one Omit Step 9 —

Method 11 Example 11-1:6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone

Step 1:4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one

Phosphorus oxychloride (1.204 mL, 7.85 mmol) was added to a stirredmixture of7-bromo-6-chloro-1-(2-isopropylphenyl)quinazoline-2,4(1H,3H)-dione(Intermediate F, 515 mg, 1.308 mmol), triethylamine (3.31 mL, 23.55mmol), and 1H-benzo[d][1,2,3]triazole (2.01 g, 16.87 mmol) inacetonitrile (15 mL). The reaction mixture was heated to 80° C. andstirred for 1 h. The reaction mixture was cooled to rt and filtered. Thefiltrate was then poured slowly into rapidly stirred water (150 mL) at˜10° C. The aqueous suspension was stirred for 15 min before beingextracted two times with EtOAc (150 mL). The organic layers werecombined, washed with brine (150 mL), dried over MgSO₄, filtered, andconcentrated in vacuo to give crude4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one.m/z (ESI) M+H: 494.0.

Step 2: tert-butyl4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (268 mg, 1.438 mmol) was added to astirred mixture of crude4-(1H-benzo[d][1,2,3]triazol-1-yl)-7-bromo-6-chloro-1-(2-isopropylphenyl)quinazolin-2(1H)-one(647 mg, 1.308 mmol) and triethylamine (3.68 mL, 26.2 mmol) in dimethylsulfoxide (6 mL). The reaction mixture was stirred at 80° C. for 30 min.The reaction mixture was diluted with EtOAc (100 mL) and washed withwater (75 mL). The organic layer was separated, washed with brine (75mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 100% EtOAcin heptane) gave tert-butyl4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (1H, s) 7.49-7.59 (2H, m)7.36-7.42 (1H, m) 7.11 (1H, d, J=7.63 Hz) 6.80 (1H, s) 3.79-3.92 (4H, m)3.62-3.73 (4H, m) 2.60 (1H, spt, J=6.80 Hz) 1.49-1.54 (9H, m) 1.22 (3H,d, J=6.85 Hz) 1.08 (3H, d, J=6.85 Hz). m/z (ESI) M+H: 561.0.

Step 3: tert-butyl4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate

tert-Butyl4-(7-bromo-6-chloro-1-(2-isopropylphenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate(115 mg, 0.205 mmol), 4-borono-5-methyl-1h-indazole (0.144 mL, 0.819mmol, Ark Pharm Inc., Arlington Heights, Ill., USA), Sphos Pd G3 (0.016mL, 0.020 mmol), and sodium carbonate (2 M aqueous, 0.409 mL, 0.819mmol) were mixed in 1,2-dimethoxyethane (1 mL) under an argon atmospherein a sealed vial. The reaction mixture was stirred at 100° C. for 24 h.The reaction mixture was cooled to rt and diluted with EtOAc (50 mL) andwater (40 mL). The organic layer was separated, washed with brine (40mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 50% (3:1EtOAc/EtOH) in heptane) gave tert-butyl4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate.m/z (ESI) M+H: 613.2.

Step 4:6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one

Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added to a stirred mixtureof tert-butyl4-(6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylate(78 mg, 0.127 mmol) in dichloromethane (1 mL). The reaction mixture wasstirred at rt for 1 h. The reaction mixture was concentrated in vacuo togive crude6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one.m/z (ESI) M+H: 513.2.

Step 5:6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone

Acryloyl chloride (10.33 μl, 0.127 mmol) was added to a stirred mixtureof6-chloro-1-(2-isopropylphenyl)-7-(5-methyl-1H-indazol-4-yl)-4-(piperazin-1-yl)quinazolin-2(1H)-one(65 mg, 0.127 mmol) and triethylamine (0.178 mL, 1.267 mmol) indichloromethane (2 mL) at 0° C. The reaction mixture was stirred at 0°C. for 20 min. Additional acryloyl chloride (5.17 μl, 0.064 mmol) wasadded, and the reaction mixture was stirred at 0° C. for another 20 min.The reaction mixture was diluted with DCM (25 mL) and quenched withsaturated aqueous sodium bicarbonate (20 mL). The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 80% (3:1EtOAc/EtOH) in heptane) gave impure product. Further chromatographicpurification of the impure product (silica gel, 0 to 100% acetone inheptane) gave the separated diastereomers.6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone(Example 11-1-1), was the first diastereomer to elute. ¹H NMR (400 MHz,CHLOROFORM-d) δ 10.28 (1H, br s) 7.94 (1H, s) 7.35-7.49 (4H, m)7.25-7.31 (2H, m) 7.11 (1H, d, J=7.67 Hz) 6.64 (1H, dd, J=16.79, 10.57Hz) 6.54 (1H, s) 6.41 (1H, dd, J=16.79, 1.87 Hz) 5.81 (1H, dd, J=10.57,1.66 Hz) 3.83-4.07 (8H, m) 2.74 (1H, spt, J=6.84 Hz) 2.13 (3H, s) 1.23(3H, d, J=6.84 Hz) 1.04 (3H, d, J=6.84 Hz). m/z (ESI) M+H: 567.2. Thesecond diastereomer to elute was further purified by columnchromatography (silica gel, 0 to 80% (3:1 EtOAc/EtOH) in heptane) togive6-chloro-7-(5-methyl-1H-indazol-4-yl)-1-(2-(2-propanyl)phenyl)-4-(4-(2-propenoyl)-1-piperazinyl)-2(1H)-quinazolinone(Example 11-1-2). ¹H NMR (400 MHz, CHLOROFORM-d) δ 10.37 (1H, br s) 7.94(1H, s) 7.34-7.50 (4H, m) 7.21-7.31 (2H, m) 7.13 (1H, d, J=7.67 Hz) 6.64(1H, dd, J=16.90, 10.68 Hz) 6.55 (1H, s) 6.41 (1H, dd, J=16.79, 1.66 Hz)5.81 (1H, dd, J=10.47, 1.55 Hz) 3.83-4.08 (8H, m) 2.70 (1H, spt, J=6.84Hz) 2.13 (3H, s) 1.22 (3H, d, J=6.84 Hz) 1.03 (3H, d, J=6.84 Hz). m/z(ESI) M+H: 567.2.

TABLE 11 Compounds 11-3 and 11-4 were prepared following the proceduredescribed in Method 11, Steps 1-5, above as follows: Ex.# ChemicalStructure Name Reagent Isomer 11-2-1

6-chloro-7-(5- methyl-1H-indazol- 4-yl)-4-((2S)-2- methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)-quinazolinone Step 2: (S)-4-n- boc-2-methyl piperazine (CNHTechnologies, Inc., Woburn, MA, USA), run at room temp overnight. 1^(st)eluting isomeric mixture 11-2-2

6-chloro-7-(5- methyl-1H-indazol- 4-yl)-4-((2S)-2- methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)-quinazolinone Step 2: (S)-4-n- boc-2-methyl piperazine (CNHTechnologies, Inc., Woburn, MA, USA), run at room temp overnight. 2^(nd)eluting isomeric mixture

Section 2—Individual Examples Example 121-(4-(7-Chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylate

To a 20 mL vial charged with tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H, 0.060 g, 0.082 mmol) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.033 g, 0.041 mmol) and 2-methyltetrahydrofuran(2.0 mL). The resulting mixture was capped and stirred at rt for 10 minbefore cyclopropylzinc bromide (0.5 M in THF, 0.820 mL, 0.410 mmol;Rieke Metals, Lincoln, Nebr., USA) was added via syringe. The reactionmixture was heated at 80° C. for 3 h before being cooled to rt andpartitioned between EtOAc (30 mL) and water (10 mL). The aqueous layerwas extracted once more with EtOAc (20 mL). The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by column chromatography (24 g of silica gel, 0 to30% acetone in heptane) to obtain tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylate.¹H NMR (CHLOROFORM-d) δ: 8.31-8.38 (m, 1H), 8.15-8.23 (m, 1H), 7.55-7.64(m, 4H), 7.39-7.47 (m, 2H), 7.29-7.38 (m, 4H), 6.99-7.09 (m, 1H),6.74-6.85 (m, 1H), 6.36-6.47 (m, 1H), 3.68-3.79 (m, 4H), 3.37-3.51 (m,4H), 2.37-2.48 (m, 1H), 1.48-1.54 (m, 9H), 1.37-1.45 (m, 1H), 1.30-1.33(m, 1H), 1.00-1.15 (m, 2H), 0.61-0.71 (m, 9H). m/z (ESI) M+H: 737.4.

Step 2:6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine

Trifluoroacetic acid (0.316 mL, 4.10 mmol) was added to a solution oftert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazine-1-carboxylatein DCM (0.7 mL). The resulting mixture was capped and stirred at rt for30 min. The reaction mixture was diluted with DCM (10 mL) and basifiedusing saturated aqueous NaHCO₃ (5 mL). The aqueous layer was extractedonce more with DCM (10 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo to obtain6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine.¹H NMR (CHLOROFORM-d) δ: 8.30-8.36 (m, 1H), 8.18-8.24 (m, 1H), 7.55-7.64(m, 4H), 7.40-7.46 (m, 2H), 7.33 (q, J=7.1 Hz, 4H), 6.97-7.09 (m, 1H),6.74-6.83 (m, 1H), 6.36-6.46 (m, 1H), 3.45-3.55 (m, 4H), 3.16-3.26 (m,4H), 2.35-2.49 (m, 1H), 1.37-1.46 (m, 1H), 1.30-1.33 (m, 1H), 1.06-1.12(m, 2H), 0.61-0.70 (m, 9H). m/z (ESI) M+H: 637.2.

Step 3:1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

To a 20 mL vial charged with6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropyl-1-(piperazin-1-yl)phthalazine(0.023 g, 0.036 mmol) was added triethylamine (16 μl, 0.114 mmol) anddichloromethane (1.0 mL). The resulting mixture was capped and stirredat rt for 10 min before acryloyl chloride (4.0 μl, 0.049 mmol) was addedvia syringe. The reaction mixture was capped and continued to stir at rtfor 20 min. The reaction was quenched with saturated aqueous NaHCO₃ (3mL) and diluted with DCM (10 mL). The aqueous layer was extracted oncemore with DCM (5 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo to obtain1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one.¹H NMR (CHLOROFORM-d) δ: 8.32-8.38 (m, 1H), 8.16-8.24 (m, 1H), 7.55-7.65(m, 4H), 7.40-7.48 (m, 2H), 7.31-7.38 (m, 4H), 6.98-7.10 (m, 1H),6.75-6.84 (m, 1H), 6.60-6.72 (m, 1H), 6.41-6.47 (m, 1H), 6.31-6.40 (m,1H), 5.72-5.82 (m, 1H), 3.79-4.08 (m, 4H), 3.44-3.62 (m, 4H), 2.38-2.49(m, 1H), 1.40-1.45 (m, 1H), 1.33-1.37 (m, 1H), 1.04-1.13 (m, 2H),0.62-0.68 (m, 9H). m/z (ESI) M+H: 691.2.

Step 4:1-(4-(7-Chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

To a 20 mL vial charged with1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopropylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(0.022 g, 0.032 mmol) was added tetrahydrofuran (2.0 mL) followed bytetrabutylammonium fluoride (1.0 M solution in THF, 0.070 mL, 0.070mmol). The vial was capped and stirred at rt for 30 min. The reactionmixture was concentrated in vacuo. The crude product was purified bycolumn chromatography (24 g of silica, 0 to 5% MeOH in DCM) to obtain1-(4-(7-chloro-4-cyclopropyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (CHLOROFORM-d) δ: 8.30-8.37 (m, 1H), 8.11-8.18 (m, 1H), 7.29-7.38(m, 1H), 6.96-7.18 (m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85 (m, 1H),6.59-6.72 (m, 1H), 6.31-6.42 (m, 1H), 5.73-5.84 (m, 1H), 3.73-4.05 (m,4H), 3.35-3.62 (m, 4H), 2.40-2.52 (m, 1H), 1.35-1.42 (m, 1H), 1.29-1.34(m, 1H), 1.03-1.14 (m, 2H). m/z (ESI) M+H: 453.2.

Example 131-(4-(4-Anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylate

To a 20 mL vial charged with tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(0.060 g, 0.082 mmol) was added dimethyl sulfoxide (2.0 mL) followed byaniline (0.075 mL, 0.820 mmol). The vial was capped and refluxed at 80°C. for 3 h. The reaction was cooled to rt and partitioned between EtOAc(30 mL) and water (10 mL). The organic layer was separated and washedwith water (2×10 mL). The organic layer was dried over MgSO₄, filtered,and concentrated in vacuo. The crude product was purified by columnchromatography (40 g of silica, 0 to 30% EtOAc in heptane) to obtaintert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylate.¹H NMR (CHLOROFORM-d) δ: 8.17-8.25 (m, 1H), 7.76-7.81 (m, 1H), 7.60-7.69(m, 5H), 7.50-7.55 (m, 2H), 7.40-7.46 (m, 2H), 7.31-7.37 (m, 5H),7.06-7.11 (m, 2H), 6.76-6.83 (m, 1H), 6.57-6.66 (m, 1H), 6.39-6.50 (m,1H), 3.66-3.81 (m, 4H), 3.32-3.43 (m, 4H), 1.51-1.53 (m, 9H), 0.69-0.75(m, 9H). m/z (ESI) M+H: 788.2.

Step 2:7-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-amine

Analogous to Example 12, step 2, the reaction of tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazine-1-carboxylatedelivered7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-amine.¹H NMR (CHLOROFORM-d) δ: 8.19-8.26 (m, 1H), 7.75-7.80 (m, 1H), 7.60-7.68(m, 5H), 7.49-7.55 (m, 2H), 7.39-7.46 (m, 3H), 7.32-7.37 (m, 5H),7.02-7.11 (m, 2H), 6.75-6.84 (m, 1H), 6.59-6.67 (m, 1H), 6.43-6.53 (m,1H), 3.35-3.47 (m, 4H), 3.16-3.27 (m, 4H), 0.70-0.76 (m, 9H). m/z (ESI)M+H: 688.2.

Step 3:1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

Analogous to Example 12, step 3, the reaction of7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-N-phenyl-4-(piperazin-1-yl)phthalazin-1-aminedelivered1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one.¹H NMR (CHLOROFORM-d) δ: 8.16-8.24 (m, 1H), 7.77-7.84 (m, 1H), 7.62-7.67(m, 4H), 7.52-7.55 (m, 1H), 7.41-7.46 (m, 3H), 7.32-7.38 (m, 6H),7.02-7.11 (m, 2H), 6.77-6.84 (m, 1H), 6.65-6.71 (m, 1H), 6.46-6.51 (m,1H), 6.30-6.39 (m, 2H), 5.73-5.81 (m, 1H), 3.86-4.05 (m, 4H), 3.37-3.53(m, 4H), 0.69-0.75 (m, 9H). m/z (ESI) M+H: 742.3.

Step 4:1-(4-(4-Anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Analogous to Example 12, step 4, the reaction of1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-(phenylamino)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-onedelivered1-(4-(4-anilino-7-chloro-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (CHLOROFORM-d) δ: 7.96-8.09 (m, 2H), 7.46-7.57 (m, 2H), 7.37-7.44(m, 1H), 7.29-7.33 (m, 1H), 7.20-7.26 (m, 1H), 6.96-7.07 (m, 1H),6.81-6.87 (m, 1H), 6.70-6.77 (m, 1H), 6.54-6.67 (m, 1H), 6.29-6.41 (m,1H), 5.68-5.82 (m, 1H), 3.74-3.96 (m, 4H), 3.12-3.43 (m, 4H). m/z (ESI)M+H: 504.2.

Example 141-(4-(7-Chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylate

Analogous to Example 12, step 1, the reaction of tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H) and cyclopentylzinc bromide (0.5 M in THF, RiekeMetals, Lincoln, Nebr.,) delivered tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylate.¹H NMR (CHLOROFORM-d) δ: 8.18-8.22 (m, 1H), 8.12-8.16 (m, 1H), 7.60-7.66(m, 2H), 7.50-7.56 (m, 2H), 7.39-7.47 (m, 2H), 7.34-7.38 (m, 2H),7.28-7.33 (m, 2H), 7.09 (br d, J=1.2 Hz, 1H), 6.75-6.82 (m, 1H),6.37-6.44 (m, 1H), 3.72-3.78 (m, 4H), 3.44-3.51 (m, 4H), 2.03-2.23 (m,4H), 1.87-1.96 (m, 2H), 1.67-1.79 (m, 3H), 1.51-1.54 (m, 9H), 0.62-0.67(m, 9H). m/z (ESI) M+H: 765.2.

Step 2:6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazine

Analogous to Example 12, step 2, the reaction of tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazine-1-carboxylatedelivered6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazine.¹H NMR (CHLOROFORM-d) δ: 8.17-8.21 (m, 1H), 8.12-8.16 (m, 1H), 7.61-7.66(m, 2H), 7.51-7.56 (m, 2H), 7.40-7.46 (m, 2H), 7.34-7.38 (m, 2H),7.29-7.33 (m, 2H), 6.99-7.08 (m, 1H), 6.74-6.82 (m, 1H), 6.37-6.45 (m,1H), 3.58-3.67 (m, 4H), 3.27-3.36 (m, 4H), 2.18-2.22 (m, 1H), 2.08-2.12(m, 2H), 1.86-1.91 (m, 3H), 1.69-1.77 (m, 3H), 0.59-0.67 (m, 9H). m/z(ESI) M+H: 665.2.

Step 3:1-(4-(6-(2-((tert-Butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

Analogous to Example 12, step 3, the reaction of6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentyl-1-(piperazin-1-yl)phthalazinedelivered1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one.¹H NMR (CHLOROFORM-d) δ: 8.18-8.25 (m, 1H), 8.13-8.17 (m, 1H), 7.61-7.67(m, 2H), 7.50-7.57 (m, 2H), 7.39-7.48 (m, 2H), 7.28-7.37 (m, 4H),6.99-7.10 (m, 1H), 6.75-6.83 (m, 1H), 6.62-6.71 (m, 1H), 6.33-6.43 (m,2H), 5.73-5.81 (m, 1H), 3.84-4.07 (m, 4H), 3.71-3.82 (m, 1H), 3.49-3.65(m, 4H), 1.80-1.96 (m, 4H), 1.67-1.77 (m, 4H), 0.62-0.67 (m, 9H). m/z(ESI) M+H: 719.2.

Step 4:1-(4-(7-Chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Analogous to Example 12, step 4, the reaction of1-(4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-7-chloro-4-cyclopentylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-onedelivered1-(4-(7-chloro-4-cyclopentyl-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (CHLOROFORM-d) δ: 8.10-8.22 (m, 2H), 7.29-7.38 (m, 1H), 6.86-6.93(m, 1H), 6.77-6.85 (m, 1H), 6.61-6.72 (m, 1H), 6.33-6.44 (m, 1H),5.74-5.85 (m, 1H), 3.82-4.05 (m, 4H), 3.75-3.82 (m, 1H), 3.40-3.63 (m,4H), 2.06-2.24 (m, 4H), 1.81-1.96 (m, 2H), 1.67-1.79 (m, 2H). m/z (ESI)M+H: 481.2.

Example 151-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylate

To a 20 mL vial charged with tert-butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H, 0.060 g, 0.082 mmol) was added piperidine (1.0 mL,10.10 mmol). The vial was capped and heated at 80° C. for 2 h. Thereaction was cooled to rt and partitioned between EtOAc (30 mL) andwater (10 mL). The organic layer was separated and washed with water(2×10 mL). The combined organic layers were dried over MgSO₄, filtered,and concentrated in vacuo to obtain tert-butyl4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylate.¹H NMR (CHLOROFORM-d) δ: 8.09-8.14 (m, 1H), 7.97-8.03 (m, 1H), 7.28-7.35(m, 1H), 6.75-6.88 (m, 2H), 3.65-3.76 (m, 4H), 3.30-3.44 (m, 8H),1.72-1.81 (m, 4H), 1.61-1.71 (m, 3H), 1.48-1.53 (m, 9H). m/z (ESI) M+H:542.2.

Step 2:2-(7-Chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenol

Analogous to Example 12, step 2, the reaction of tert-butyl4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(piperidin-1-yl)phthalazin-1-yl)piperazine-1-carboxylatedelivered2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenol.¹H NMR (CHLOROFORM-d) δ: 8.09-8.13 (m, 1H), 7.95-8.03 (m, 1H), 7.28-7.38(m, 1H), 6.83-6.89 (m, 1H), 6.75-6.82 (m, 1H), 3.39-3.48 (m, 4H),3.31-3.38 (m, 4H), 3.12-3.21 (m, 4H), 1.75-1.80 (m, 4H), 1.64-1.69 (m,2H). m/z (ESI) M+H: 442.2.

Step 3:1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Analogous to Example 12, step 3, the reaction of2-(7-chloro-1-(piperazin-1-yl)-4-(piperidin-1-yl)phthalazin-6-yl)-3-fluorophenoldelivered1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(1-piperidinyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (CHLOROFORM-d) δ: 8.08-8.15 (m, 1H), 7.98-8.05 (m, 1H), 7.29-7.39(m, 1H), 6.86-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.70 (m, 1H),6.30-6.43 (m, 1H), 5.72-5.84 (m, 1H), 3.77-4.05 (m, 4H), 3.40-3.56 (m,4H), 3.32-3.38 (m, 4H), 1.73-1.85 (m, 4H), 1.64-1.70 (m, 2H). m/z (ESI)M+H: 496.2.

Example 161-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylate

A dry 50 mL rbf was charged with phenol (0.130 g, 1.381 mmol) andtetrahydrofuran (3.0 mL). The mixture was cooled to 0° C. beforepotassium t-butoxide (0.153 g, 1.367 mmol) was added. The mixture wasstirred at 0° C. for 10 min before being warmed to rt and stirred for 30min. tert-Butyl4-(6-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-4,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate H, 0.100 g, 0.137 mmol) was added, and the resultingmixture was heated at 60° C. for 2 h. The reaction was cooled to rt andquenched with water. The resulting mixture was partitioned between EtOAc(30 mL) and water (15 mL). The aqueous layer was extracted once morewith EtOAc (20 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo. The crude product was purified bycolumn chromatography (40 g of silica, 10 to 50% acetone) to obtaintert-butyl4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylate:m/z (ESI) M+H: 551.2.

Step 2:2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol

Analogous to Example 12, step 2, the reaction of4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxyphthalazin-1-yl)piperazine-1-carboxylatedelivered.2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenol.¹H NMR (CHLOROFORM-d) δ: 8.37-8.42 (m, 1H), 8.14-8.19 (m, 1H), 7.37-7.45(m, 2H), 7.29-7.34 (m, 1H), 7.19-7.25 (m, 2H), 6.89-6.98 (m, 1H),6.76-6.87 (m, 4H), 3.36-3.45 (m, 4H), 3.13-3.22 (m, 4H). m/z (ESI) M+H:451.2.

Step 3:1-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

Analogous to Example 12, step 3, the reaction of2-(7-chloro-4-phenoxy-1-(piperazin-1-yl)phthalazin-6-yl)-3-fluorophenoldelivered1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-phenoxy-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (CHLOROFORM-d) δ: 8.41-8.45 (m, 1H), 8.17-8.20 (m, 1H), 7.40-7.45(m, 2H), 7.28-7.37 (m, 2H), 7.20-7.26 (m, 1H), 6.78-6.87 (m, 2H),6.59-6.70 (m, 1H), 6.31-6.41 (m, 1H), 5.97-6.06 (m, 1H), 5.74-5.81 (m,1H), 3.76-4.03 (m, 4H), 3.38-3.53 (m, 4H). m/z (ESI) M+H: 505.2.

Examples 17-1 and 17-2(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one(Example 17-1) and(2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one(Example 17-2)

Step 1: tert-Butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A slurry of tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D, 459 mg, 1.02 mmol), (3-methoxynaphthalen-1-yl)boronicacid (823 mg, 4.07 mmol) and cesium carbonate (1.33 g, 4.07 mmol) in amixture of 1,4-dioxane (8 mL) and water (2 mL) was degassed with anargon stream. Tetrakis(triphenylphosphine)palladium (118 mg, 0.10 mmol)was added, and the mixture was again degassed with an Argon stream. Thereaction mixture was sealed and heated at 100° C. for 23 h. The reactionwas allowed to cool to rt, diluted with brine (60 mL), and extracted twotimes with EtOAc. The combined organic layers were dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography (eluent: 0-2% MeOH in DCM) to provide tert-butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate.m/z (ESI) M+H: 528.0.

Step 2:5-Chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole

To a solution of tert-butyl4-(5-chloro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate(327 mg, 0.56 mmol) in DCM (6 mL) was added trifluoroacetic acid (1.04mL, 13.9 mmol) via syringe. The resulting yellow solution was stirred atrt for 4 h and then was concentrated. The residue was purified by silicagel chromatography (eluent: 0-25% MeOH in DCM) to provide the mono-TFAsalt of5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole.m/z (ESI) M+H: 428.0.

Step 3:(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one

To a solution of5-chloro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(74 mg of the mono-TFA salt, 0.14 mmol) andtrans-4-dimethylaminocrotonoic acid hydrochloride (38 mg, 0.23 mmol) inDMA (2 mL) was added thionyl chloride (41 □L, 0.69 mmol) via syringe.The resulting brown solution was stirred at rt for 2.5 h. The reactionmixture was quenched with water (50 mL) and extracted with 8:1 DCM/MeOH.The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluent: 0-15% MeOH in DCM) to provide(2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.94 (d, J=8.4 Hz, 1H),7.46-7.55 (m, 2H), 7.27-7.35 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 6.61-6.72(m, 2H), 3.94 (s, 3H), 3.80-3.93 (m, 4H), 3.62-3.68 (m, 4H), 3.07 (d,J=4.3 Hz, 2H), 2.18 (s, 6H). m/z (ESI) M+H: 539.2.

Step 4:(2E)-1-(4-(5-Chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one

To a solution of(2E)-1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one(23.5 mg, 0.044 mmol) in 1,2-dichloroethane (4 mL) at 0° C. was addedboron tribromide (1.0 M in hexanes, 218 □L, 0.22 mmol) dropwise viasyringe. The resulting yellow slurry was stirred at 0° C. for 2.75 h andthen quenched with saturated aqueous NaHCO₃ (4 mL). The mixture wasextracted two times with a 4:1 mixture of DCM/MeOH. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography (eluent: 0-18% MeOH inDCM) to provide(2E)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-(dimethylamino)-2-buten-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.10 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.40-7.46 (m, 1H), 7.19-7.30 (m, 3H), 7.07 (d, J=2.4 Hz, 1H),6.62-6.71 (m, 2H), 3.80-3.93 (m, 4H), 3.62-3.69 (m, 4H), 3.07 (d, J=4.1Hz, 2H), 2.17 (s, 6H). m/z (ESI) M+H: 525.0.

Examples 18-1 to 18-31-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one.(Example 18-1) and2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one(Example 18-2) and1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one(Example 18-3)

Step 1:1-(4-(5-Chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one

A vial was charged with a solution of1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate 0, 29 mg, 0.06 mmol) in tert-butanol (0.4 mL) and water(0.4 mL). Phenol (5.7 mg, 0.06 mmol), DABCO (20.3 mg, 0.18 mmol) andformaldehyde (37% aqueous solution, 24 □L, 0.24 mmol) were addedsequentially. The resulting solution was sealed and heated at 55° C. for29 h. The reaction was cooled to rt and partitioned between water (6 mL)and 10:1 DCM/MeOH. The organic layer was separated, and the aqueouslayer was extracted two more times with 10:1 DCM/MeOH. The combinedorganic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluent: 0-3.5% MeOH in DCM) to provide1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H), 7.94 (d, J=8.2 Hz, 1H),7.47-7.55 (m, 2H), 7.25-7.34 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 5.43 (br.s, 1H), 5.20 (br. s, 1H), 5.14 (t, J=5.8 Hz, 1H), 4.12 (d, J=5.7 Hz,2H), 3.94 (s, 3H), 3.78-3.85 (m, 4H), 3.54-3.66 (m, 4H). m/z (ESI) M+H:512.0.

Step 2:2-(Bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-oneand1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one

To a solution of1-(4-(5-chloro-7-fluoro-6-(3-methoxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-(hydroxymethyl)-2-propen-1-one(17.1 mg, 0.033 mmol) in 1,2-dichloroethane (4 mL) at 0° C. was addedboron tribromide solution (1.0 M in hexanes, 167 □L, 0.17 mmol) dropwisevia syringe. The resulting slurry was stirred at 0° C. for 40 min beforebeing quenched with saturated aqueous NaHCO₃ (5 mL). The mixture wasextracted twice with a 4:1 mixture of DCM/MeOH. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography (eluent: 0-7% MeOH inDCM) to give two products.

First-Eluting Peak:

2-(bromomethyl)-1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (br. s, 1H), 8.13 (s, 1H), 7.80 (d,J=8.2 Hz, 1H), 7.40-7.47 (m, 1H), 7.19-7.29 (m, 3H), 7.07 (d, J=2.4 Hz,1H), 5.78 (s, 1H), 5.41 (s, 1H), 4.38 (s, 2H), 3.84-3.93 (m, 4H),3.62-3.72 (m, 4H). m/z (ESI) M+H: 560.0

Second-Eluting Peak:

1-(4-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-(hydroxymethyl)prop-2-en-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (br. s, 1H), 8.11 (s, 1H), 7.79 (d,J=8.2 Hz, 1H), 7.37-7.48 (m, 1H), 7.17-7.28 (m, 3H), 7.07 (d, J=2.4 Hz,1H), 5.43 (br. s, 1H), 5.20 (br. s, 1H), 5.07-5.14 (m, 1H), 4.12 (br. s,2H), 3.78-3.86 (m, 4H), 3.57-3.66 (m, 4H). m/z (ESI) M+H: 498.0

Examples 19-1 to 19-31-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one(Example 19-1) and1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one(Example 19-2) and1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one(Example 19-3)

Step 1: tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A slurry of Intermediate D (232 mg, 0.51 mmol),5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(535 mg, 1.95 mmol, see synthesis below) and cesium carbonate (636 mg,1.95 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL) wasdegassed with an Argon stream. Tetrakis(triphenylphosphine)palladium (59mg, 0.05 mmol) was added and the mixture was again degassed with anArgon stream. The reaction mixture was sealed and heated at 100° C. for18 h. The reaction was allowed to cool to rt and partitioned betweenbrine (40 mL) and EtOAc. The aqueous later was twice extracted withEtOAc and the combined organic layers were dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gelchromatography (eluent: 0-4.5% DCM/MeOH) to provide tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate.LCMS-ESI (POS.) m/z: 518.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.90(br. s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.31 (d, J=1.4 Hz, 1H), 6.99(d, J=2.2 Hz, 1H), 3.83 (s, 3H), 3.61-3.69 (m, 4H), 3.54-3.60 (m, 4H),1.45 (s, 9H).

5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A suspension of 7-bromo-5-methoxy-1H-indazole (1.00 g, 4.40 mmol, ArkPharm Inc. Arlington Heights, Ill., USA), potassium acetate (1.30 g,13.2 mmol) and bis(pinacolato)diboron (1.23 g, 4.84 mmol) in 1,4-dioxane(18 mL) was degassed with an Argon stream. Added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex withdichloromethane (108 mg, 0.13 mmol) and again degassed with an Argonstream. The reaction mixture was sealed and heated at 80° C. for 2 d.The reaction was allowed to cool to rt and partitioned between water (50mL) and EtOAc. The aqueous layer was twice extracted with EtOAc and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluent: 2-65% EtOAc/heptane) to provide5-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.LCMS-ESI (POS.) m/z: 275.1 (M+H)⁺.

Step 2: tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylateand tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate(115 mg, 0.22 mmol) in THF (5 mL) was added sodium hydride (60%dispersion in mineral oil, 44.5 mg, 1.1 mmol). After 10 min, iodomethane(69 □L, 1.1 mmol) was added and the reaction stirred at rt for anadditional 15 min before being partitioned between saturated aqueousammonium chloride (10 mL) and DCM. The aqueous layer was extracted twicewith DCM and the combined organic layers were dried over anhydroussodium sulfate and concentrated to afford a mixture of tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylateand tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate.The crude mixture was used in the subsequent step without purification.LCMS-ESI (POS.) m/z: 532.0 (M+H)⁺.

Step 3:5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate J) and5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate K)

To a solution of the crude mixture of mixture of tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylateand tert-butyl4-(5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate(143 mg) in DCM (6 mL) was added trifluoroacetic acid (484 □L, 6.5 mmol)via syringe. The resulting solution was stirred at rt for 25 min andthen was concentrated. The residue was purified by silica gelchromatography (eluent: 0-25% DCM/MeOH).

First-Eluting Peak:

The mono-TFA salt of5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate J). LCMS-ESI (POS.) m/z: 432.0 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.99 (d,J=2.4 Hz, 1H), 3.84 (s, 3H), 3.67-3.76 (m, 4H), 3.56 (s, 3H), 3.36-3.42(m, 4H).

Second-Eluting Peak:

The mono-TFA salt of5-chloro-7-fluoro-6-(5-methoxy-2-methyl-2H-indazol-7-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate K). LCMS-ESI (POS.) m/z: 432.0 (M+H)⁺.

Step 4:1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

To an ice-cooled slurry of the mono-TFA salt of Intermediate J (108 mg,0.20 mmol) in DCM (5 mL) was added DIPEA (104 DL, 0.60 mmol) followed byacryloyl chloride (24 □L, 0.30 mmol) dropwise via syringe. The resultingsolution was stirred at 0° C. for 3 h and was then quenched withsaturated aqueous NaHCO₃ solution (15 mL) and extracted twice with DCM.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(eluent: 0-7% DCM/MeOH) to provide1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.LCMS-ESI (POS.) m/z: 486.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s,1H), 8.02 (s, 1H), 7.33 (d, J=2.2 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.85(dd, J=16.6, 10.6 Hz, 1H), 6.18 (dd, J=16.7, 2.3 Hz, 1H), 5.76 (dd,J=10.5, 2.3 Hz, 1H), 3.85-3.95 (m, 4H), 3.84 (s, 3H), 3.62-3.72 (m, 4H),3.56 (s, 3H).

Step 5:1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

To an ice-cooled solution of1-(4-(5-chloro-7-fluoro-6-(5-methoxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one(72.5 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was added borontribromide solution (1.0 M in hexanes, 746 □L, 0.75 mmol) dropwise viasyringe. The resulting slurry was stirred at 0° C. for 3.75 h and wasthen quenched with saturated aqueous NaHCO₃ solution (5 mL) andextracted twice with a 4:1 mixture of DCM/MeOH. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography (eluent: 0-6%DCM/MeOH) to provide1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-1-methyl-1H-indazol-7-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one.LCMS-ESI (POS.) m/z: 472.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s,1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.2 Hz, 1H), 6.81-6.91 (m,2H), 6.18 (dd, J=16.7, 2.5 Hz, 1H), 5.76 (dd, J=10.4, 2.4 Hz, 1H),3.81-3.94 (m, 4H), 3.62-3.70 (m, 4H), 3.52 (s, 3H).

For the synthesis of1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.

Using Intermediate K from Step 3, Steps 4 and 5 were performed as aboveto deliver1-(4-(5-chloro-7-fluoro-6-(5-hydroxy-2-methyl-2H-indazol-7-yl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.LCMS-ESI (POS.) m/z: 472.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s,1H), 8.11 (s, 1H), 8.01 (s, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.77-6.90 (m,2H), 6.18 (dd, J=16.7, 2.5 Hz, 1H), 5.76 (dd, J=10.4, 2.2 Hz, 1H), 4.03(s, 3H), 3.80-3.94 (m, 4H), 3.58-3.66 (m, 4H).

Example 201-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone

Step 1:4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one

To a solution of 4-((tert-butyldiphenylsilyl)oxy)-2-methylenebutanoicacid (101 mg, 0.29 mmol, prepared according to Pihko, P. M., J. Org.Chem., 2006, 71, 2538-2541 and Greaney, M. F., Org. Lett., 2007, 9,1931-1934) in DCM (2 mL) was added a 2M solution of oxalyl chloride(0.21 mL, 0.43 mmol) at 0° C. followed by a catalytic amount of DMF (5□L). The reaction mixture was allowed to warm to rt and stirred for 2 h.The reaction mixture was concentrated in vacuo then diluted with DCM (1mL) and added to a solution of5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)-3-(piperazin-1-yl)benzo[c]isothiazole(Intermediate N, 122 mg, 0.29 mmol), triethylamine (0.20 mL, 1.43 mmol),and DCM (2 mL). The reaction mixture was allowed to warm to rt and DMAP(2 mg, 0.016 mmol) was added. The reaction mixture was stirred at rt for15 h then concentrated in vacuo and purified by silica gel columnchromatography (eluent: 0-50% EtOAc:heptanes) to give4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one.¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.94 (d, J=8.0 Hz, 1H),7.63-7.61 (m, 4H), 7.52-7.49 (m, 2H), 7.47-7.40 (m, 6H), 7.33-7.28 (m,2H), 7.20-7.19 (m, 1H), 5.37 (s, 1H), 5.24 (s, 1H), 3.94 (s, 3H),3.83-3.76 (m, 6H), 3.53 (br s, 2H), 3.31 (s, 4H), 1.01 (s, 9H). m/z(ESI) M+H: 764.

Step 2:1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone

To a solution of4-((tert-butyldiphenylsilyl)oxy)-1-(4-(5-chloro-7-fluoro-6-(3-methoxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazin-1-yl)-2-methylenebutan-1-one(85 mg, 0.11 mmol) and DCM (2 mL) was added a 2M solution of BBr₃ (0.28mL, 0.56 mmol) in DCM at 0° C. The reaction mixture was quenched withwater, concentrated in vacuo and purified by silica gel columnchromatography (elution with 0-50% heptane/3:1 EtOAc:EtOH) to afford1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-4-hydroxy-2-methylidene-1-butanone.¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (br s, 1H), 8.11 (s, 1H), 7.80 (d, J=12Hz, 1H), 7.43 (m, 1H), 7.26-7.20 (m, 3H), 7.07 (s, 1H), 5.32 (s, 1H),5.16 (s, 1H), 3.83 (br s, 4H), 3.63 (br s, 4H), 3.53 (t, J=8.0 Hz, 2H),2.42 (t, J=8.0 Hz, 2H). ¹⁹FNMR (377 MHz, DMSO-d₆) δ −123.8 (s, 1F). m/z(ESI) M+H: 512.

Example 211-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-onewas made from Intermediate D by Method 1 using7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(synthesis below) with the following changes: in Step 7, S-Phos Pd G3,aqueous potassium carbonate, and DME were used; in Step 8-1, TFA/DCM wasused; in Step 8-2, DCE was used as solvent; and in Step 8-3, borontribromide solution (1.0 M in DCE) was used to give1-(4-(5-chloro-7-fluoro-6-(7-hydroxy-5-quinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.¹H NMR (400 MHz, CDCl₃) δ 8.81 (dd, J=4.2, 1.3 Hz, 1H) 7.72-7.78 (m, 2H)7.64 (s, 1H) 7.28 (d, J=2.2 Hz, 1H) 7.16 (dd, J=8.4, 4.3 Hz, 1H)6.56-6.66 (m, 1H) 6.40 (dd, J=16.8, 1.6 Hz, 1H) 5.78-5.87 (m, 1H) 4.01(br. s., 2H) 3.89 (br. s., 2H) 3.50-3.60 (m, 4H). ¹⁹F NMR (376 MHz,CDCl₃) δ −121.33 (s, 1F). MS (ESI, +ve) m/z: 469.1 (M+1)⁺.

7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

A solution of 5-bromo-7-methoxyquinoline (0.407 g, 1.71 mmol, OxChem,Wood Dale, Ill., USA),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.912 g,3.59 mmol), PdCl₂(dppf) (0.051 g, 0.070 mmol), and potassium acetate(0.503 g, 5.13 mmol) in DMF (9 mL) was stirred at 90° C. for 1 h then at100° C. for 45 min. The reaction mixture was diluted with EtOAc (100mL), and washed with saturated, aqueous sodium bicarbonate (2×75 mL).The organic layer was separated, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The crude product was adsorbed onto silica andpurified via column chromatography (silica gel, 0-80% heptane/EtOAc) togive 7-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline.MS (ESI, +ve) m/z: 286.1 (M+1)⁺.

Example 221-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-4-(2-propenoyl)-2-piperazinecarboxylicacid

To a solution of methyl4-acryloyl-1-(5-chloro-7-fluoro-6-(3-hydroxynaphthalen-1-yl)benzo[c]isothiazol-3-yl)piperazine-2-carboxylate(Example 7-3, 0.022 g, 0.042 mmol) in THF/EtOH (1:1; 6 mL) at 0° C. wasadded NaOH (5 N aq.; 1.0 mL, 5.0 mmol), and the resulting mixture wasstirred at 0° C. for 5 min. The reaction was acidified with 5 N HCl at0° C., extracted with EtOAc, and purified by HPLC to afford1-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-4-(2-propenoyl)-2-piperazinecarboxylicacid. m/z (ESI, +ve) 512.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 3.14-3.28(m, 1H) 3.52-3.87 (m, 3H) 4.15-5.03 (m, 2H) 5.15-5.23 (m, 1H) 5.77-5.83(m, 1H) 6.13-6.24 (m, 1H) 6.86 (br. s., 1H) 7.06-7.12 (m, 1H) 7.20-7.30(m, 3H) 7.38-7.49 (m, 1H) 7.76-7.84 (m, 1H) 8.07-8.13 (m, 1H) 9.98 (br.s., 1H) 13.42 (br. s., 1H).

Example 231-(4-(5-chloro-6-(5-cyclopropyl-1H-indazol-4-yl)-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Example 23 was made as described in Method 1 using(5-cyclopropyl-1H-indazol-4-yl)boronic acid (see synthesis below) inStep 7, and omitting Step 8-3. m/z (ESI, +ve) 482.0 (M+H)+. ¹H NMR (400MHz, DMSO-d₆) δ 12.92-13.19 (1H, m), 8.02-8.21 (1H, m), 7.47-7.60 (2H,m), 7.02-7.09 (1H, m), 6.80-6.93 (1H, m), 6.15-6.25 (1H, m), 5.71-5.82(1H, m), 3.80-3.96 (4H, m), 3.60-3.72 (4H, m), 1.55-1.74 (1H, m),0.72-0.79 (2H, m), 0.58-0.71 (2H, m).

(5-cyclopropyl-1H-indazol-4-yl)boronic acid

Step 1: 2-bromo-1-cyclopropyl-4-fluorobenzene

To a 2-L round bottom flask at ambient temperature was added2-bromo-4-fluoro-1-iodobenzene (22 g, 73.1 mmol) and cyclopropylboronicacid (12.6 g, 146 mmol) in cyclopentyl methyl ether (1.1 L). Na₂CO₃ (2 Maq.; 183 mL) was added, and the reaction was degassed with N₂-gas for 20minutes. Tetrakis (8.45 g, 7.31 mmol) was added, and the reaction wasdegassed again with N₂-gas for 20 minutes. The reaction mixture was thentransferred to a 5-L autoclave under N₂-atm and heated to 130° C. for 40h. The reaction mixture was cooled to ambient temperature, filteredthrough a Celite pad, and washed with diethyl ether (200 mL). To thefiltrate was added water (500 mL), and the organic layer was separated.The aqueous layer was extracted with diethyl ether (2×300 mL), and thecombined organic layers were dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude material was adsorbed ontoa plug of silica gel and chromatographically purified (silica gel, 100%petroleum ether) to provide 2-bromo-1-cyclopropyl-4-fluorobenzene. GC-MSm/z: 214/216 ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.23 (m, 1H), 6.95 (dt,J=7.0, 1.5 Hz, 2H), 2.09 (ddd, J=13.8, 8.5, 5.4 Hz, 1H), 1.12-0.88 (m,2H), 0.76-0.50 (m, 2H).

Step 2: 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde

To a 500-mL round-bottom flask was added2-bromo-1-cyclopropyl-4-fluorobenzene (6.5 g, 30.2 mmol) intetrahydrofuran (130 mL) under N₂-atm. LDA (18.1 mL, 36.3 mmol, 2 M inTHF, 1.2 equiv) was added dropwise at −78° C. (internal temperaturemaintained between −65° C. to −70° C.), and the reaction mixture wasstirred for 1 h. DMF (6 mL) was then added dropwise to the reactionmixture (internal temperature maintained between −65° C. to −70° C.),and the reaction was stirred for a further 3 h at −78° C. The reactionwas quenched with saturated aqueous ammonium chloride solution (100 mL)and slowly warmed to ambient temperature. The mixture was diluted withdiethyl ether (200 mL), and the organic layer separated and washed witha brine solution (2×50 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crudematerial was adsorbed onto a plug of silica gel and chromatographicallypurified (silica gel, 0-2% EtOAc/hexane) to provide2-bromo-3-cyclopropyl-6-fluorobenzaldehyde. GC-MS m/z: 242 ¹H NMR (400MHz, CDCl₃) δ 10.43 (d, J=1.5 Hz, 1H), 7.26-7.12 (m, 1H), 7.06 (t, J=9.3Hz, 1H), 2.15 (td, J=8.4, 4.3 Hz, 1H), 1.17-0.94 (m, 2H), 0.78-0.52 (m,2H).

Step 3: 4-bromo-5-cyclopropyl-1H-indazole

To a 100-mL sealed tube was added2-bromo-3-cyclopropyl-6-fluorobenzaldehyde (4 g, 16.5 mmol) andhydrazine hydrate (4.0 mL, 82 mmol) in ethylene glycol (40 mL). Thereaction was stirred for 2 h at 90° C. and then heated to 150° C. for 16h. The reaction mixture was cooled to ambient temperature, and ice coldwater (40 mL) and EtOAc (50 mL) were added. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (2×40 mL). Thecombined organic layers were washed with water (2×40 mL) and brinesolution (40 mL), dried over anhydrous aqueous sodium sulfate, andconcentrated in vacuo. The crude material was adsorbed onto a plug ofsilica gel and chromatographically purified (silica gel, 0-20%EtOAc/hexane) to provide 4-bromo-5-cyclopropyl-1H-indazole. The compoundwas purified by reverse phase preparative liquid chromatography (YMC:C₁₈, 150×20 mm, 5 μm; mobile phase: 0.1% TFA in water and acetonitrile;flow rate: 15 mL/min) to afford pure compound. MS (ESI positive ion)m/z: 237/239.0 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 13.31 (s, 1H), 7.97(s, 1H), 7.46 (d, J=8.6 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 2.21 (tt,J=8.5, 5.3 Hz, 1H), 1.24-0.87 (m, 2H), 0.93-0.33 (m, 2H).

Step 4: 5-cyclopropyl-1H-indazol-4-yl)boronic acid

To a 100-mL round-bottomed flask was added4-bromo-5-cyclopropyl-1H-indazole (0.62 g, 2.6 mmol) andbis(pinacolato)diboron (0.996 g, 3.92 mmol) in 1,4-dioxane (25 mL);potassium acetate (0.77 g, 7.84 mmol) was added, and the reactionmixture was degassed with N₂-gas for 10 minutes. PdCl₂(dppf).DCM adduct(0.213 g, 0.261 mmol) was added to the reaction mixture; the reactionmixture was again degassed with N₂-gas for 10 minutes then heated to100° C. for 16 h. The reaction mixture was cooled to ambienttemperature, filtered through a Celite pad, and washed with EtOAc (50mL). The filtrate was concentrated in vacuo, and the crude material wasadsorbed onto a plug of silica gel and chromatographically purified(silica gel, 0-50% EtOAc/hexane). The compound was further purified byreverse phase preparative liquid chromatography (Grace column; 0-70%MeCN/water) to provide 5-cyclopropyl-1H-indazol-4-yl)boronic acid. MS(ESI positive ion) m/z: 285.2 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 12.88(s, 1H), 8.13 (q, J=1.3 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 6.83 (dd,J=8.8, 1.4 Hz, 1H), 2.78-2.60 (m, 1H), 1.38 (d, J=1.4 Hz, 12H),1.07-0.85 (m, 2H), 0.75-0.48 (m, 2H).

Example 241-(4-(5-Chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Step 1:1-(5-Chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methylisoquinolin-3-amine

To a solution of tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D, 30 mg, 0.067 mmol) in tetrahydrofuran (0.6 mL) at 0° C.was added a solution of isopropylmagnesium chloride (2.0 M solution intetrahydrofuran, 0.050 mL, 0.100 mmol). The mixture was stirred for 5min before zinc chloride (1.9 M solution in 2-methyltetrahydrofuran,0.053 mL, 0.100 mmol) was added, and the reaction mixture was warmed tort and stirred for 40 min. The reaction mixture was then transferred toa vial containing Sphos Pd G3 (5.76 mg, 6.66 μmol) and tert-butyl(1-bromoisoquinolin-3-yl)(methyl)carbamate (24.7 mg, 0.073 mmol, seesynthesis below) and heated to 70° C. overnight. The crude reaction wasdiluted with sat. aq. NH₄Cl (50 mL) and EtOAc (50 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel column chromatography eluting with 6-20% MeOHin DCM afforded1-(5-chloro-7-fluoro-3-(piperazin-1-yl)benzo[c]isothiazol-6-yl)-N-methylisoquinolin-3-amine.m/z (ESI, +ve) 428.1 (M+H)⁺.

Synthesis of tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate

To a solution of 1-bromoisoquinolin-3-amine (200 mg, 0.897 mmol,Maybridge Chemical Co., Altrincham, UK) in tetrahydrofuran (5 mL) at rtwas added sodium bis(trimethylsilyl)amide (1M solution intetrahydrofuran, 1.79 mL, 1.79 mmol). The mixture was stirred for 10 minbefore a solution of Boc-anhydride (0.208 mL, 0.897 mmol) in THF (1 mL)was added. The reaction mixture was stirred for 5 min before beingdiluted with sat. aq. NH₄Cl (50 mL) and EtOAc (50 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel column chromatography eluting with 0-20%EtOAc in heptane afforded tert-butyl (1-bromoisoquinolin-3-yl)carbamate.m/z (ESI, +ve) 345.0 (M+Na)⁺.

To a solution of tert-butyl (1-bromoisoquinolin-3-yl)carbamate (140 mg,0.433 mmol) in tetrahydrofuran (3 mL) at rt was added sodium hydride(60% dispersion in mineral oil, 22.52 mg, 0.563 mmol). The mixture wasstirred for 15 min before methyl iodide (0.033 mL, 0.520 mmol) wasadded. After stirring overnight the reaction was diluted with sat. aq.NH₄Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, driedover Na₂SO₄, filtered, and concentrated. Purification by silica gelcolumn chromatography eluting with 0-10% EtOAc in heptane affordedtert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate. ¹H NMR (400 MHz,METHANOL-d₄) δ 8.25 (d, J=8.61 Hz, 1H), 7.88-7.95 (m, 2H), 7.79 (t,J=7.5 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 3.42 (s, 3H), 1.54 (s, 9H). m/z(ESI, +ve) 359.1 (M+H)⁺.

Step 2:1-(4-(5-Chloro-7-fluoro-6-(3-(methylamino)-1-isoquinolinyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Procedure analogous to Method 1, Step 8-2. Purified by silica gel columnchromatography eluting with 0-14% MeOH in DCM over 15 min. ¹H NMR (400MHz, METHANOL-d₄) δ 7.90 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.43 (t, J=7.4Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 6.72-6.84 (m,1H), 6.67 (s, 1H), 6.15-6.28 (m, 1H), 5.68-5.81 (m, 1H), 3.87-3.97 (m,4H), 3.63 (m, 4H), 2.90 (s, 3H). m/z (ESI, +ve) 482.0 (M+H)⁺.

Example 251-(4-(6-(3-Amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(6-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate

Procedure analogous to Example 25, Step 1, using a solution of 1.3 Misopropylmagnesium lithium chloride in THF in place ofisopropylmagnesium chloride solution and bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidodicarbonate (synthesis below) in placeof tert-butyl (1-bromoisoquinolin-3-yl)(methyl)carbamate. m/z (ESI, +ve)614.2 (M+H)⁺.

Synthesis of bis(2-methyl-2-propanyl)(1-bromo-3-isoquinolinyl)-2-imidodicarbonate

To a solution of 1-bromoisoquinolin-3-amine (1.0 g, 4.48 mmol, MaybridgeChemical Co., Altrincham, UK) in DCM (50 mL) at 0° C. was addedBoc-anhydride (3.12 mL, 13.45 mmol) and DMAP (0.055 g, 0.448 mmol). Thereaction was warmed to rt and stirred overnight. The reaction mixturewas then diluted with sat. aq. NH₄Cl (100 mL) and DCM (50 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, andconcentrated. Purification by silica gel column chromatography elutingwith 0-10% EtOAc in heptane over 15 min affordedbis(2-methyl-2-propanyl) (1-bromo-3-isoquinolinyl)-2-imidodicarbonate.¹H NMR (400 MHz, METHANOL-d₄) δ 8.36 (d, J=8.5 Hz, 1H), 8.03 (d, J=8.1Hz, 1H), 7.77-7.92 (m, 3H), 1.44 (s, 18H). m/z (ESI, +ve) 267.0 (M+H)⁺.

Step 2:1-(4-(6-(3-Amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Procedure analogous to Method 1, Steps 8-1 and 8-2 with the use of TFAin DCM in place of 4M HCl in dioxane/MeOH in Step 8-1. Purified bysilica gel column chromatography eluting with 0-12% MeOH in DCM. Thismaterial was then subjected to SFC purification: diol column (21.2×250mm, 5 μm) using 17% (20 mM NH₃ in MeOH) in supercritical CO₂ (total flowrate was 7 g/min) to afford1-(4-(6-(3-amino-1-isoquinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one.¹H NMR (400 MHz, METHANOL-d₄) δ 7.85 (s, 1H), 7.53 (d, J=8.5 Hz, 1H),7.39 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H),6.82 (s, 1H), 6.71 (dd, J=10.8, 16.8 Hz, 1H), 6.2 (dd, J=1.5, 16.8 Hz,1H), 5.70 (dd, J=1.5, 10.8 Hz, 1H), 3.82-3.93 (m, 4H), 3.50-3.66 (m,4H). m/z (ESI, +ve) 468.0 (M+H)⁺.

Example 261-(4-(6-(2-Amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Step 1: tert-Butyl4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate

A solution of tert-butyl4-(6-bromo-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazine-1-carboxylate(Intermediate D, 320 mg, 0.710 mmol), 1,1,1,2,2,2-hexabutyldistannane(824 mg, 1.420 mmol), and tetrakis(triphenylphosphine)palladium(0) (82mg, 0.071 mmol, Strem Chemicals Inc., NewburyPort, Mass., USA) inN,N-dimethylacetamide (5 mL) was heated in a sealed vial in themicrowave at 160° C. for 40 min. The reaction mixture was diluted withsat. aq. NaHCO₃ (50 mL), brine (50 mL) and EtOAc (100 mL). The organiclayer separated, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel column chromatography eluting with 0-30%EtOAc in heptane afforded tert-butyl4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate.m/z (ESI, +ve) 662.2 (M+H)⁺.

Step 2: 2-Methyl-2-propanyl4-(6-(2-(bis(((2-methyl-2-propanyl)oxy)carbonyl)amino)-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate

A solution of di-tert-butyl (4-bromoquinolin-2-yl)-2-imidodicarbonate(19.2 mg, 0.045 mmol, prepared in analogous fashion tobis(2-methyl-2-propanyl) (1-bromo-3-isoquinolinyl)-2-imidodicarbonate inExample 26 using 4-bromoquinolin-2-amine (Ark Pharm Inc. ArlingtonHeights, Ill., USA) as starting material, tert-butyl4-(5-chloro-7-fluoro-6-(tributylstannyl)benzo[c]isothiazol-3-yl)piperazine-1-carboxylate(20 mg, 0.030 mmol), tetrakis(triphenylphosphine)palladium(0) (6.99 mg,6.05 μmol, Strem Chemicals Inc., NewburyPort, Mass., USA), copper(I)iodide (1.153 mg, 6.05 μmol) and cesium fluoride (13.79 mg, 0.091 mmol)in DMF (0.5 mL) was heated in a sealed vial at 60° C. for 30 min. Thecrude reaction was diluted with sat. aq. NaHCO₃ (50 mL) and EtOAc (100mL). The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated. Purification by silica gel column chromatography elutingwith 0-50% EtOAc in heptane afforded 2-methyl-2-propanyl4-(6-(2-(bis(((2-methyl-2-propanyl)oxy)carbonyl)amino)-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinecarboxylate.m/z (ESI, +ve) 714.2 (M+H)⁺.

Step 3:1-(4-(6-(2-amino-4-quinolinyl)-5-chloro-7-fluoro-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one

Procedure analogous to Method 1, Steps 8-1 and 8-2 with the use of TFAin DCM in place of 4 M HCl in dioxane/MeOH in Step 8-1. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.90 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.42-7.49 (m, 1H),7.10 (d, J=8.0 Hz, 1H), 7.03-7.08 (m, J=7.6 Hz, 1H), 6.67-6.81 (m, 2H),6.19 (dd, J=1.8, 16.6 Hz, 1H), 5.72 (dd, J=1.8, 10.6 Hz, 1H), 3.87-3.93(m, 4H), 3.56-3.66 (m, 4H). m/z (ESI, +ve) 468.0 (M+H)⁺.

Example 271-(4-(3-(2-Fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one

Step 1: 6,7-Dihydropyrido[2,3-d]pyridazine-5,8-dione

Hydrazine (1.26 mL, 40.2 mmol) was added to a stirred solution of2,3-pyridinedicarboxylic anhydride (4.00 g, 26.8 mmol) in ethanol (100mL). The reaction mixture was refluxed for 16 h before being cooled tort and concentrated in vacuo to give crude6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione that was used directly inthe next step. m/z (ESI) M+H: 164.1.

Step 2: 5,8-Dichloropyrido[2,3-d]pyridazine

Pyridine (4.57 mL, 53.7 mmol) was added to a mixture of crude6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione (4.38 g, 26.8 mmol) inphosphorus(v) oxychloride (20.1 mL, 215 mmol). The reaction mixture wasstirred at 100° C. for 2 h. The reaction mixture was cooled and pouredslowly into rapidly stirred water (250 mL) at ˜10° C. The aqueoussuspension was stirred for 15 min before being extracted with EtOAc (250mL). The organic layer was separated, washed with brine (200 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 100% EtOAc in heptane)gave 5,8-dichloropyrido[2,3-d]pyridazine. ¹H NMR (400 MHz, CHLOROFORM-d)δ 9.41 (1H, dd, J=4.30, 1.56 Hz) 8.65 (1H, dd, J=8.41, 1.56 Hz) 8.02(1H, dd, J=8.41, 4.30 Hz). m/z (ESI) M+H: 200.0.

Step 3: 3,5-Dichloropyrido[2,3-d]pyridazin-8(7H)-one and3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one

N-Chlorosuccinimide (1268 mg, 9.50 mmol, TCI America, Portland, Oreg.,USA) was added to a stirred solution of5,8-dichloropyrido[2,3-d]pyridazine (950 mg, 4.75 mmol) in acetic acid(20 mL) and the reaction mixture was heated to 100° C. for 16 h.Additional N-chlorosuccinimide (1268 mg, 9.50 mmol, TCI America,Portland, Oreg., USA) was added, and the reaction mixture was stirred at100° C. for another 4 h. Additional N-chlorosuccinimide (634 mg, 4.75mmol, TCI America, Portland, Oreg., USA) was added, and the reactionmixture was stirred for another 4 h. The reaction mixture was thendiluted with water (75 mL) and extracted three times with EtOAc (100mL). The combined organic layers were washed with brine (150 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 75% EtOAc in heptane) gavea regioisomeric mixture of 3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-onecompound and 3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one. m/z (ESI)M+H: 215.9.

Step 4: 3,5,8-Trichloropyrido[2,3-d]pyridazine

Pyridine (2.024 mL, 23.79 mmol) was added to the regioisomeric mixtureof 3,5-dichloropyrido[2,3-d]pyridazin-8(7H)-one and3,8-dichloropyrido[2,3-d]pyridazin-5(6H)-one (2.57 g, 11.90 mmol) inphosphorus oxychloride (8.90 mL, 95 mmol). The reaction mixture wasstirred at 100° C. for 1.5 h. The reaction mixture was cooled and pouredslowly into rapidly stirred water (150 mL) at ˜10° C. The aqueoussuspension was stirred for 15 min before being extracted with EtOAc (200mL). The organic layer was separated, washed with brine (150 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 50% EtOAc in heptane) gave3,5,8-trichloropyrido[2,3-d]pyridazine. ¹H NMR (400 MHz, CHLOROFORM-d) δ9.27 (1H, d, J=2.35 Hz) 8.58 (1H, d, J=2.35 Hz). m/z (ESI) M+H: 233.9.

Step 5: tert-Butyl4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate

1-Boc-piperazine (278 mg, 1.494 mmol) was added to a stirred mixture of3,5,8-trichloropyrido[2,3-d]pyridazine (292 mg, 1.245 mmol) andtriethylamine (0.350 mL, 2.491 mmol) in dimethyl sulfoxide (5 mL). Thereaction mixture was stirred at rt for 3 h before being diluted withEtOAc (75 mL), and washed with saturated aqueous sodium bicarbonate (75mL). The organic layer was separated, washed with brine (50 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 25% acetone in heptane)gave tert-butyl4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate, thefirst of two regioisomers to elute. ¹H NMR (400 MHz, CHLOROFORM-d) δ9.01 (1H, d, J=2.54 Hz) 8.43 (1H, d, J=2.54 Hz) 4.04-4.15 (4H, m)3.64-3.70 (4H, m) 1.50 (9H, s). m/z (ESI) M+H: 384.0.

Step 6: tert-Butyl4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate

tert-Butyl4-(3,5-dichloropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate (199mg, 0.518 mmol), 2-isopropylphenylboronic acid (93 mg, 0.570 mmol, AlfaAesar, Haver Hill, Mass., USA), tetrakis(triphenylphosphine)palladium(59.8 mg, 0.052 mmol, Strem Chemicals Inc., NewburyPort, Mass., USA),and sodium carbonate (2 M aqueous, 1.036 mL, 2.072 mmol) were mixed in1,4-dioxane (4 mL) under an argon atmosphere. The reaction mixture wasstirred at 40° C. for 16 h. The reaction mixture was cooled to rt,diluted with EtOAc (50 mL), and washed with water (40 mL). The organiclayer was separated, washed with brine (50 mL), dried over MgSO₄,filtered, and concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0 to 50% EtOAc in heptane) gave a mixture ofstarting material and desired product. The mixture was re-subjected tothe original reaction conditions using less 2-isopropylphenylboronicacid (56 mg, 0.342 mmol, Alfa Aesar, Haver Hill, Mass., USA). Themixture was stirred at 40° C. for 16 h. Additional2-isopropylphenylboronic acid (28 mg, 0.171 mmol, Alfa Aesar, HaverHill, Mass., USA) was added, and the reaction mixture was stirred foranother 6 h. The reaction mixture was cooled to rt, diluted with EtOAc(50 mL), and washed with water (40 mL). The organic layer was separated,washed with brine (50 mL), dried over MgSO₄, filtered, and concentratedin vacuo. Chromatographic purification of the residue (silica gel, 0 to50% EtOAc in heptane) gave tert-butyl4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.95 (1H, d, J=2.35 Hz) 7.72 (1H, d,J=2.54 Hz) 7.45-7.53 (2H, m) 7.26-7.33 (1H, m) 7.16-7.21 (1H, m)4.04-4.23 (4H, m) 3.66-3.73 (4H, m) 2.67 (1H, spt, J=6.75 Hz) 1.48 (9H,s) 1.16 (3H, d, J=6.85 Hz) 1.03 (3H, d, J=6.85 Hz). m/z (ESI) M+H:468.2.

Step 7: tert-Butyl4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate

Methyllithium (1.6 M solution in diethyl ether, 0.137 mL, 0.219 mmol)was added to a stirred solution of tert-butyl4-(3-chloro-5-(2-isopropylphenyl)pyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate(93 mg, 0.199 mmol) in tetrahydrofuran (1 mL) at −78° C. The reactionmixture was stirred at −78° C. for 5 min before being allowed to warm to0° C. and stirred for 30 min. The reaction mixture was cooled back downto −78° C. and additional methyllithium (1.6 M solution in diethylether, 0.068 mL, 0.109 mmol) was added. The reaction mixture was stirredat −78° C. for 5 min before being allowed to warm to 0° C. and stirredfor another 15 min. The reaction mixture was quenched with water (20 mL)and extracted with EtOAc (30 mL). The organic layer was separated,washed with brine (20 mL), dried over MgSO₄, filtered, and concentratedin vacuo to give crude tert-butyl4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate.m/z (ESI) M+H: 484.3.

4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (45.0 mg,0.198 mmol) was added to a stirred mixture of crude tert-butyl4-(3-chloro-5-(2-isopropylphenyl)-2-methyl-1,2-dihydropyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate(96 mg, 0.198 mmol) in dichloromethane (2 mL). The reaction mixture wasstirred at rt for 10 min. The reaction mixture was diluted with DCM (30mL) and washed with water (20 mL). The organic layer was separated,dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 50% EtOAc in heptane) gavetert-butyl4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate.¹H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (1H, s) 7.51-7.55 (2H, m)7.32-7.37 (1H, m) 7.22-7.27 (1H, m) 4.08-4.25 (4H, m) 3.71-3.79 (4H, m)2.87 (3H, s) 2.73 (1H, spt, J=6.68 Hz) 1.54 (9H, s) 1.21 (3H, d, J=6.85Hz) 1.07 (3H, d, J=6.85 Hz). m/z (ESI) M+H: 482.1.

Step 8: tert-Butyl4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate

tert-Butyl4-(3-chloro-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate(78 mg, 0.162 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (101 mg,0.647 mmol, Combi-Blocks), Sphos Pd G3 (14.00 mg, 0.016 mmol) and sodiumcarbonate (2 M aqueous, 0.324 mL, 0.647 mmol) were mixed in1,2-dimethoxyethane (1 mL) under an argon atmosphere and then heated at80° C. for 2.5 h. The reaction mixture was cooled, diluted with EtOAc(30 mL), and washed with water (25 mL). The organic layer was separated,washed with brine (25 mL), dried over MgSO₄, filtered, and concentratedin vacuo. Chromatographic purification of the residue (silica gel, 0 to50% EtOAc in heptane) gave tert-butyl4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate(66 mg, 0.118 mmol, 73.1% yield). m/z (ESI) M+H: 558.2.

Step 9:3-Fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol

Trifluoroacetic acid (0.2 mL, 2.68 mmol) was added to a stirred solutionof tert-butyl4-(3-(2-fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazine-1-carboxylate(64 mg, 0.115 mmol) in dichloromethane (0.5 mL). The reaction mixturewas stirred at rt for 30 min. The reaction mixture was diluted with DCM(30 mL) and quenched with saturated aqueous sodium bicarbonate (20 mL).The organic layer was separated, dried over MgSO₄, filtered, andconcentrated in vacuo to give crude3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol.m/z (ESI) M+H: 458.1.

Step 10:1-(4-(3-(2-Fluoro-6-hydroxyphenyl)-5-(2-isopropylphenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)prop-2-en-1-one

Acryloyl chloride (9.45 μl, 0.116 mmol) was added to a stirred mixtureof3-fluoro-2-(5-(2-isopropylphenyl)-2-methyl-8-(piperazin-1-yl)pyrido[2,3-d]pyridazin-3-yl)phenol(53 mg, 0.116 mmol) and triethylamine (0.049 mL, 0.348 mmol) indichloromethane (1 mL) at 0° C. The reaction mixture was stirred at 0°C. for 10 min. The reaction mixture was diluted with DCM (25 mL) andquenched with saturated aqueous sodium bicarbonate (20 mL). The organiclayer was separated, dried over MgSO₄, filtered, and concentrated invacuo. Chromatographic purification of the residue (silica gel, 0 to100% EtOAc in heptane) gave1-(4-(3-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-(2-(2-propanyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-piperazinyl)-2-propen-1-one.¹H NMR (400 MHz, CHLOROFORM-d) δ 9.51 (0.6H, br s) 8.98 (0.4H, br s)7.63 (0.4H, s) 7.58 (0.6H, s) 7.35-7.43 (2H, m) 7.10-7.26 (3H, m) 6.78(1H, dd, J=16.63, 8.22 Hz) 6.59-6.71 (2H, m) 6.36 (1H, dd, J=16.82, 1.57Hz) 5.78 (1H, dd, J=10.56, 1.37 Hz) 4.10-4.38 (4H, m) 3.80-4.03 (4H, m)2.60-2.72 (1H, m) 2.61 (1.2H, s) 2.59 (1.8H, s) 0.91-1.08 (6H, m). m/z(ESI) M+H: 512.3.

Example 281-(4-(7-Chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-oneand1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

A mixture of α-methylbenzylzinc bromide (0.5 M in THF, 492 μl, 0.246mmol), tetrakis(triphenylphosphine)palladium (5.68 mg, 4.92 μmol, StremChemicals Inc., NewburyPort, Mass., USA), and1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate I, 22 mg, 0.049 mmol) was stirred at 60° C. in a sealedvial for 16 h. The reaction mixture was concentrated and chromatographicpurification of the residue (silica gel, 0 to 100% EtOAc in heptane)gave a mixture of1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1R)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-oneand 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-((1S)-1-phenylethyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one. ¹H NMR(400 MHz, METHANOL-d₄) δ 8.27 (1H, s) 8.15 (0.33H, s) 8.10 (0.67H, s)7.19-7.31 (5H, m) 7.10-7.16 (1H, m) 6.86 (1H, dd, J=16.73, 10.66 Hz)6.62-6.78 (2H, m) 6.27 (1H, dd, J=16.82, 1.96 Hz) 5.80 (1H, dd, J=10.66,1.86 Hz) 4.94-5.01 (1H, m) 3.93-4.03 (4H, m) 3.49-3.60 (4H, m) 1.81 (3H,d, J=7.04 Hz). m/z (ESI) M+H: 517.1.

Example 291-(4-(7-Chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one

4-Fluorobenzylzinc chloride (0.5 M in THF, 0.089 mL, 0.044 mmol) wasadded to a stirred mixture of1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(Intermediate I, 18 mg, 0.040 mmol) andtetrakis(triphenylphosphine)palladium (4.65 mg, 4.02 μmol, StremChemicals Inc., NewburyPort, Mass., USA) in tetrahydrofuran (0.1 mL) ina sealed vial under an argon atmosphere. The reaction mixture wasstirred at rt for 2 h before being heated to 40° C. for 3 h. Additional4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added, and thereaction mixture was stirred at 40° C. for another 16 h. Additional4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added, and thereaction mixture was heated to 60° C. and stirred for 6 h. The reactionmixture was concentrated in vacuo. Chromatographic purification of theresidue (silica gel, 0 to 100% EtOAc in heptane) gave1-(4-(7-chloro-4-(4-fluorobenzyl)-6-(2-fluoro-6-hydroxyphenyl)-1-phthalazinyl)-1-piperazinyl)-2-propen-1-one.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (1H, s) 8.19 (1H, s) 7.26-7.34 (3H,m) 6.98 (2H, t, J=8.71 Hz) 6.69-6.91 (3H, m) 6.28 (1H, dd, J=16.92, 1.86Hz) 5.82 (1H, dd, J=10.56, 1.76 Hz) 4.54-4.65 (2H, m) 3.99 (4H, m) 3.58(4H, m). m/z (ESI) M+H: 521.2.

Examples 30 and 312-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluorophenol(Example 30) and2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluorophenol(Example 31)

Step 1: 1,4,6,7-Tetrachlorophthalazine (Intermediate L)

Pyridine (431 μl, 5.28 mmol) was added to a stirred mixture of6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G, 610 mg,2.64 mmol) in phosphorus oxychloride (2.4 mL, 26.4 mmol). The reactionmixture was heated to 100° C. for 2 h then cooled and poured slowly intorapidly stirred water (75 mL) at ˜10° C. The resulting suspension wasfiltered, and the solid was washed with water to give1,4,6,7-tetrachlorophthalazine. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.43(2H, s). m/z (ESI) M+H: 266.9.

Step 2: tert-Butyl4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate (IntermediateM)

1-Boc-piperazine (340 mg, 1.824 mmol) was added to a stirred mixture of1,4,6,7-tetrachlorophthalazine (Intermediate L, 543 mg, 2.027 mmol) andtriethylamine (0.846 mL, 6.08 mmol) in dichloromethane (8 mL). Thereaction mixture was stirred at rt for 2 days. Additional1-boc-piperazine (340 mg, 1.824 mmol) was added, and the reactionmixture was stirred at rt for another 23 h. The reaction mixture wasquenched with saturated aqueous sodium bicarbonate (20 mL) and extractedwith DCM (30 mL). The organic layer was separated, washed with brine (20mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 50% EtOAcin heptane) gave tert-butyl4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate. ¹H NMR (400MHz, Chloroform-d) δ 8.35 (1H, s) 8.12 (1H, s) 3.68-3.75 (4H, m)3.45-3.52 (4H, m) 1.51 (9H, s). m/z (ESI) M+H: 417.0.

Step 3: tert-Butyl4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate

tert-Butyl 4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate M, 95 mg, 0.227 mmol),tetrakis(triphenylphosphine)palladium (26.3 mg, 0.023 mmol, StremChemicals Inc., NewburyPort, Mass., USA), phenylboronic acid (27.7 mg,0.227 mmol), and sodium carbonate (2 M aqueous, 0.341 mL, 0.682 mmol)were mixed in 1,4-dioxane (1 mL) in a sealed vial under an argonatmosphere. The reaction mixture was stirred at 40° C. for 24 h.Additional tetrakis(triphenylphosphine)palladium (26.3 mg, 0.023 mmol)and phenylboronic acid (13.5 mg, 0.113 mmol) were added, and thereaction mixture was stirred at 40° C. for another 24 h. The reactionmixture was quenched with saturated aqueous sodium bicarbonate (20 mL)and extracted with EtOAc (25 mL). The organic layer was separated,washed with brine (20 mL), dried over MgSO₄, filtered, and concentratedin vacuo. Chromatographic purification of the residue (silica gel, 0 to100% EtOAc in heptane) gave tert-butyl4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate. ¹H NMR(400 MHz, Chloroform-d) δ 8.13 (1H, s) 8.07 (1H, s) 7.62-7.67 (2H, m)7.50-7.55 (3H, m) 3.65-3.74 (4H, m) 3.44-3.53 (4H, m) 1.47 (9H, s). m/z(ESI) M+H: 459.1.

Step 4: 6,7-Dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine

tert-Butyl4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazine-1-carboxylate (68 mg,0.148 mmol) was stirred in trifluoroacetic acid (1 mL, 13.46 mmol) at rtfor 20 min. The reaction mixture was quenched with saturated aqueoussodium bicarbonate (20 mL) and extracted two times with DCM (25 mL). Theorganic layer was separated, dried over MgSO₄, filtered, andconcentrated in vacuo to give crude6,7-dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine that was useddirectly in the next step. m/z (ESI) M+H: 359.0.

Step 5:1-(4-(6,7-Dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

Acryloyl chloride (0.013 mL, 0.162 mmol) was added to a stirred mixtureof 6,7-dichloro-1-phenyl-4-(piperazin-1-yl)phthalazine (53 mg, 0.148mmol) and triethylamine (0.062 mL, 0.443 mmol) in dichloromethane (1mL). The reaction mixture was stirred at rt for 30 min. The reactionmixture was quenched with saturated aqueous sodium bicarbonate (15 mL)and extracted with DCM (20 mL). The organic layer was separated, driedover MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 100% EtOAc in heptane)gave1-(4-(6,7-dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one.¹H NMR (400 MHz, Cloroform-d) δ 8.20 (1H, s) 8.14 (1H, s) 7.66-7.75 (2H,m) 7.54-7.62 (3H, m) 6.66 (1H, dd, J=16.63, 10.37 Hz) 6.37 (1H, dd,J=16.82, 1.96 Hz) 5.78 (1H, dd, J=10.56, 1.96 Hz) 3.85-4.04 (1H, m)3.53-3.72 (1H, m). m/z (ESI) M+H: 431.2.

Step 6:2-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluorophenoland2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluorophenol

1-(4-(6,7-Dichloro-4-phenylphthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one(43 mg, 0.104 mmol), 2-fluoro-6-hydroxyphenylboronic acid (17.84 mg,0.114 mmol, Combi-Blocks Inc., San Diego, Calif., USA), Sphos Pd G3(9.00 mg, 10.40 μmol), and sodium carbonate (2 M aqueous, 0.156 mL,0.312 mmol) were mixed in 1,2-dimethoxyethane (0.5 mL) in a sealed vialunder an argon atmosphere. The reaction mixture was stirred at 60° C.for 3 h. Additional 2-fluoro-6-hydroxyphenylboronic acid (8.92 mg, 0.057mmol, Combi-Blocks Inc., San Diego, Calif., USA) and SPhos Pd G3 (9.00mg, 10.40 μmol) were added, and the reaction mixture was stirred at 60°C. for another 2 h. The reaction mixture was quenched with saturatedaqueous sodium bicarbonate (15 mL) and extracted with EtOAc (20 mL). Theorganic layer was separated, washed with brine (10 mL), dried overMgSO₄, filtered, and concentrated in vacuo. Chromatographic purificationof the residue (silica gel, 0 to 100% EtOAc in heptane) gave a mixtureof the two regioisomeric products. Reverse phase preparativechromatography (XBridge Prep C18 5 μm OBD, 150×30 mm; 35 to 55% (0.1%TFA in water) in (0.1% TFA in acetonitrile); flow rate=30 mL/min) gavethe separated regioisomeric products. The fractions containing theindividual regioisomers were neutralized with saturated aqueous sodiumbicarbonate and extracted with DCM, and the organic extracts wereconcentrated in vacuo. The separated regioisomers were furtherindividually purified by column chromatography (silica gel, 0 to 100%EtOAc in heptane).2-(1-(4-acryloyl-1-piperazinyl)-7-chloro-4-phenyl-6-phthalazinyl)-3-fluorophenol(Example 30), was the first regioisomer to elute from the reverse phasepreparative chromatography. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (1H,s) 8.06 (1H, s) 7.62-7.69 (2H, m) 7.45-7.51 (3H, m) 7.24-7.32 (1H, m)6.81-6.90 (1H, m) 6.75 (1H, t, J=8.41 Hz) 6.65 (1H, dd, J=16.82, 10.56Hz) 6.38 (1H, dd, J=16.82, 1.76 Hz) 5.79 (1H, dd, J=10.56, 1.76 Hz)3.86-4.02 (4H, m) 3.57-3.76 (4H, m). m/z (ESI) M+H: 489.0.2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-phenyl-6-phthalazinyl)-3-fluorophenol(Example 31), was the second regioisomer to elute from the reverse phasecolumn. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (1H, s) 8.12 (1H, s)7.68-7.73 (2H, m) 7.53-7.58 (3H, m) 7.30 (1H, br td, J=8.22, 6.65 Hz)6.88 (1H, d, J=8.22 Hz) 6.78 (1H, t, J=8.61 Hz) 6.57 (1H, dd, J=16.82,10.56 Hz) 6.28 (1H, dd, J=16.73, 1.66 Hz) 5.71 (1H, dd, J=10.56, 1.56Hz) 3.78-3.89 (4H, m) 3.51-3.73 (4H, m). m/z (ESI) M+H: 489.1.

Examples 32 and 332-(1-(4-Acryloyl-1-piperazinyl)-7-chloro-4-methoxy-6-phthalazinyl)-3-fluorophenol(Example 32) and2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-methoxy-6-phthalazinyl)-3-fluorophenol(Example 33)

Examples 32 and 33 were prepared in an analogous method to Examples 30and 31 with the exception of Step 3, which was changed as follows:

Step 3: tert-Butyl4-(6,7-dichloro-4-methoxyphthalazin-1-yl)piperazine-1-carboxylate

tert-Butyl 4-(4,6,7-trichlorophthalazin-1-yl)piperazine-1-carboxylate(Intermediate M, 198 mg, 0.474 mmol) and sodium methoxide (25% solutionin methanol, 2 mL, 8.75 mmol) were mixed in a sealed vial. The reactionmixture was stirred at 60° C. for 2 h. The reaction mixture was quenchedwith saturated aqueous sodium bicarbonate (25 mL) and extracted withEtOAc (25 mL). The organic layer was separated, washed with brine (20mL), dried over MgSO₄, filtered, and concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 50% EtOAcin heptane) gave tert-butyl4-(6,7-dichloro-4-methoxyphthalazin-1-yl)piperazine-1-carboxylate. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.29 (1H, s) 8.08 (1H, s) 4.22 (3H, s)3.68-3.73 (4H, m) 3.33-3.38 (4H, m) 1.51 (9H, s). m/z (ESI) M+H: 413.1.

From step 6: First eluting regioisomer:2-(1-(4-acryloyl-1-piperazinyl)-7-chloro-4-methoxy-6-phthalazinyl)-3-fluorophenol(Example 32) ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.23 (1H, s) 8.11 (1H, s)7.32 (1H, td, J=8.31, 6.46 Hz) 6.88 (1H, d, J=8.22 Hz) 6.77-6.83 (1H, m)6.65 (1H, dd, J=16.82, 10.56 Hz) 6.37 (1H, dd, J=16.82, 1.76 Hz) 5.79(1H, dd, J=10.47, 1.86 Hz) 4.18 (3H, s) 3.79-4.05 (4H, m) 3.34-3.54 (4H,m). m/z (ESI) M+H: 443.1.

Second eluting regioisomer:2-(4-(4-acryloyl-1-piperazinyl)-7-chloro-1-methoxy-6-phthalazinyl)-3-fluorophenol(Example 33)¹H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (1H, s) 8.01 (1H, s)7.32 (1H, td, J=8.27, 6.55 Hz) 6.89 (1H, d, J=8.22 Hz) 6.77-6.83 (1H, m)6.60 (1H, dd, J=17.02, 10.56 Hz) 6.30 (1H, dd, J=16.82, 1.76 Hz) 5.75(1H, dd, J=10.56, 1.76 Hz) 4.22 (3H, s) 3.67-3.98 (4H, m) 3.25-3.55 (4H,m). m/z (ESI) M+H: 443.1.

Example 34 1-(4-Acryloyl-1-piperazinyl)-4-benzyl-6,7-dichlorophthalazine

Example 34 was prepared in an analogous method to Examples 30 and 31with the exception of step 6, which was omitted, and Steps 2 and 3,which were changed as follows:

Steps 2 and 3: tert-Butyl4-(4-benzyl-6,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate

Benzylzinc bromide (0.5 M in THF, 1.926 mL, 0.963 mmol) was added to asealed vial containing 1,4,6,7-tetrachlorophthalazine (Intermediate L,258 mg, 0.963 mmol) and tetrakis(triphenylphosphine)palladium (111 mg,0.096 mmol, Strem Chemicals Inc., NewburyPort, Mass., USA) under anargon atmosphere. The reaction mixture was stirred at rt for 16 h.1-Boc-piperazine (1.79 g, 9.63 mmol) was added, and the reaction mixturewas stirred at 60° C. for 5 h. The reaction mixture was quenched withsaturated aqueous sodium bicarbonate (40 mL) and extracted with EtOAc(50 mL). The organic layer was separated, washed with brine (40 mL),dried over MgSO₄, filtered, and concentrated in vacuo. Chromatographicpurification of the residue (silica gel, 0 to 50% EtOAc in heptane) gavetert-butyl4-(4-benzyl-6,7-dichlorophthalazin-1-yl)piperazine-1-carboxylate. ¹H NMR(400 MHz, CHLOROFORM-d) δ 8.11 (1H, s) 8.10 (1H, s) 7.27-7.35 (4H, m)7.20-7.25 (1H, m) 4.59 (2H, s) 3.69-3.74 (4H, m) 3.44-3.49 (4H, m) 1.52(9H, s). m/z (ESI) M+H: 473.1. m/z (ESI) M+H: 473.1.

From Step 5:1-(4-acryloyl-1-piperazinyl)-4-benzyl-6,7-dichlorophthalazine

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.13 (1H, s) 8.12 (1H, s) 7.28-7.36(4H, m) 7.20-7.26 (1H, m) 6.65 (1H, dd, J=16.82, 10.56 Hz) 6.37 (1H, dd,J=16.82, 1.57 Hz) 5.78 (1H, dd, J=10.56, 1.56 Hz) 4.61 (2H, s) 3.83-4.01(4H, m) 3.48-3.62 (4H, m). m/z (ESI) M+H: 427.1.

Example 35 and 362-(1-(4-Acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-phthalazinyl)-3-fluorophenol(Example 35) and2-(4-(4-acryloyl-1-piperazinyl)-1-benzyl-7-chloro-6-phthalazinyl)-3-fluorophenol(Example 36)

1-(4-(4-Benzyl-6,7-dichlorophthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one

(Example 34, 35 mg, 0.082 mmol), 2-fluoro-6-hydroxyphenylboronic acid(12.77 mg, 0.082 mmol, Combi-Blocks Inc., San Diego, Calif., USA), SPhosPd G3 (7.09 mg, 8.19 μmol), and sodium carbonate (2 M aqueous, 0.123 mL,0.246 mmol) were mixed in 1,2-dimethoxyethane (0.3 mL) in a sealed vialunder an argon atmosphere. The reaction mixture was stirred at 60° C.for 1 h. The reaction mixture was quenched with saturated aqueous sodiumbicarbonate (15 mL) and extracted with EtOAc (20 mL). The organic layerwas separated, washed with brine (10 mL), dried over MgSO₄, filtered,and concentrated in vacuo. Chromatographic purification of the residue(silica gel, 0 to 100% EtOAc in heptane) gave a mixture of the tworegioisomeric products. Reverse phase preparative chromatography(XBridge Prep C18 5 μm OBD, 150×30 mm; 20 to 90% (0.1% TFA in water) in(0.1% TFA in acetonitrile); flow rate=30 mL/min) gave the partiallyseparated regioisomeric products. The fractions containing theregioisomers were neutralized with saturated aqueous sodium bicarbonateand extracted with DCM, and the organic extracts were concentrated invacuo.2-(1-(4-acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-phthalazinyl)-3-fluorophenol(Example 35), was the first regioisomer to elute during reverse phasepreparative chromatography, and contained approximately 36% of thesecond regioisomer to elute. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.13 (1H,s) 8.11 (1H, s) 7.12-7.37 (6H, m) 6.91 (1H, d, J=8.22 Hz) 6.77 (1H, t,J=8.61 Hz) 6.64 (1H, dd, J=16.82, 10.56 Hz) 6.37 (1H, dd, J=16.82, 1.76Hz) 5.79 (1H, dd, J=10.56, 1.96 Hz) 4.55 (2H, s) 3.34-4.01 (8H, m). m/z(ESI) M+H: 503.1.2-(4-(4-acryloyl-1-piperazinyl)-1-benzyl-7-chloro-6-phthalazinyl)-3-fluorophenol(Example 36), was the second regioisomer to elute. ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.12 (1H, s) 8.05 (1H, s) 7.26-7.36 (5H, m) 7.19-7.24(1H, m) 6.93 (1H, d, J=8.41 Hz) 6.76 (1H, t, J=8.31 Hz) 6.58 (1H, dd,J=16.82, 10.76 Hz) 6.28 (1H, dd, J=16.82, 1.76 Hz) 5.75 (1H, dd,J=10.56, 1.76 Hz) 4.54 (2H, s) 3.32-3.93 (8H, m). m/z (ESI) M+H: 503.1.

Example 371-(4-acryloyl-1-piperazinyl)-4-benzyl-6-chloro-7-(5-methyl-1H-indazol-4-yl)phthalazineand1-(4-acryloyl-1-piperazinyl)-4-benzyl-7-chloro-6-(5-methyl-1H-indazol-4-yl)phthalazine

Example 37 was prepared in an analogous method to Examples 35 and 36with 5-methyl-1h-indazol-4-yl boronic acid (Combi-Blocks Inc., SanDiego, Calif., USA) in place of 2-fluoro-6-hydroxyphenylboronic acid. Inthis embodiment the two regioisomeric products were not separated. ¹HNMR (400 MHz, CHLOROFORM-d) δ 8.23 (0.6H, s) 8.22 (0.4H, s) 8.02 (0.4H,s) 8.00 (0.6H, s) 7.19-7.57 (8H, m) 6.68 (0.4H, dd, J=16.82, 10.56 Hz)6.60 (0.6H, dd, J=16.82, 10.56 Hz) 6.38 (0.4H, dd, J=16.63, 1.76 Hz)6.32 (0.6H, dd, J=16.82, 1.76 Hz) 5.79 (0.4H, dd, J=10.56, 1.76 Hz) 5.73(0.6H, dd, J=10.56, 1.76 Hz) 4.67 (1.2H, s) 4.60 (0.8H, s) 3.74-4.06(4H, m) 3.46-3.70 (4H, m) 2.21 (1.8H, s) 2.06 (1.2H, s). m/z (ESI) M+H:523.

Example 386-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)-4-(4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one

The starting material for Example 38 was prepared using Method 8 Steps1-4 with reagents 2,5,6-trichloronicotinic acid (Step 1),aminomethylcyclopropane (Step 2), 2-fluoro-6-hydroxyphenylboronic acid(Step 4, Combi-Blocks Inc., San Diego, Calif., USA), and sodiumcarbonate (Step 4).

Step 1:7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

tert-Butylchlorodiphenylsilane (0.036 mL, 0.139 mmol) was added to astirred mixture of6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione(42 mg, 0.116 mmol) and triethylamine (0.065 mL, 0.464 mmol) inacetonitrile (0.5 mL). The reaction mixture was stirred at rt for 1 h.The reaction mixture was quenched with saturated aqueous NH₄Cl (25 mL)and extracted with EtOAc (30 mL). The organic layer was separated,washed with brine (25 mL), dried over MgSO₄, filtered, and concentratedin vacuo to give crude7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionethat was used directly in the next step. m/z (ESI) M+H: 599.8.

Step 2:4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

Phosphorus oxychloride (0.087 mL, 0.933 mmol) was added to a stirredmixture of crude7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione(70 mg, 0.117 mmol), triethylamine (0.295 mL, 2.099 mmol), and1H-benzo[d][1,2,3]triazole (167 mg, 1.400 mmol) in acetonitrile (2 mL).The reaction mixture was stirred at 80° C. for 4 h. The reaction mixturewas concentrated in vacuo. The resulting residue was taken up in1,2-dichloroethane (2 mL), and triethylamine (0.295 mL, 2.099 mmol) and1-(piperazin-1-yl)prop-2-en-1-one (32.7 mg, 0.233 mmol, eNovationChemicals LLC, Bridgewater, N.J., USA) were added. The reaction mixturewas stirred at rt for 16 h. Additional triethylamine (0.148 mL, 1.050mmol) and 1-(piperazin-1-yl)prop-2-en-1-one (32.7 mg, 0.233 mmol,eNovation Chemicals LLC, Bridgewater, N.J., USA) were added, and thereaction mixture was stirred at rt for 1 h before being heated to 60° C.and stirred for 4 h. The reaction mixture was diluted with saturatedaqueous NaHCO₃ (40 mL) and extracted with DCM (50 mL). The organic layerwas separated, dried over MgSO₄, filtered, and concentrated in vacuo.The resulting residue was again taken up in 1,2-dichloroethane (2 mL),and triethylamine (0.295 mL, 2.099 mmol) and1-(piperazin-1-yl)prop-2-en-1-one (32.7 mg, 0.233 mmol, eNovationChemicals LLC, Bridgewater, N.J., USA) were added. The reaction mixturewas stirred at 60° C. for 6 h. The reaction mixture was diluted withsaturated aqueous NaHCO₃ (40 mL) and extracted with DCM (50 mL). Theorganic layer was separated, dried over MgSO₄, filtered, andconcentrated in vacuo. Chromatographic purification of the residue(silica gel, 0 to 100% (3:1 EtOAc/EtOH) in heptane) gave4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-onethat was taken on in the next step without further purification. m/z(ESI) M+H: 721.8.

Step 3:4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.025mL, 0.025 mmol) was added to a stirred mixture of4-(4-acryloylpiperazin-1-yl)-7-(2-((tert-butyldiphenylsilyl)oxy)-6-fluorophenyl)-6-chloro-1-(cyclopropylmethyl)pyrido[2,3-d]pyrimidin-2(1H)-one(6 mg, 8.31 μmol) in tetrahydrofuran (0.2 mL). The reaction mixture wasstirred at rt for 20 min before being concentrated in vacuo.Chromatographic purification of the residue (silica gel, 0 to 100% (3:1EtOAc/EtOH) in heptane) gave6-chloro-1-(cyclopropylmethyl)-7-(2-fluoro-6-hydroxyphenyl)-4-(4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (1H, s) 7.26-7.33 (1H, m) 6.82(1H, d, J=8.29 Hz) 6.71 (1H, t, J=8.91 Hz) 6.51 (1H, dd, J=16.79, 10.57Hz) 6.30 (1H, dd, J=16.79, 1.45 Hz) 5.72 (1H, dd, J=10.47, 1.55 Hz) 4.15(2H, br d, J=6.43 Hz) 3.69-3.90 (8H, m) 1.14-1.27 (4H, m) 0.73-0.88 (1H,m). m/z (ESI) M+H: 483.8.

Separated Compound Examples

Racemic SM/ Ex.# Chemical Structure Name separation conditions 2-5-1

1-((3S)-4-(5-chloro-6-(3- hydroxy-1-naphthalen- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one or1-((3R)-4-(5-chloro-6-(3- hydroxy-1-naphthalen- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one 2-5/SFC(Chiralpak AD-H, 20 × 150 mm, 5 μm, 55% MeOH/CO₂, 80 mL/min, 100 bar).2-5-2

1-((3R)-4-(5-chloro-6-(3- hydroxy-1-naphthalen- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one or1-((3S)-4-(5-chloro-6-(3- hydroxy-1-naphthalen- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one 2-5/SFC(Chiralpak AD-H, 20 × 150 mm, 5 μm, 55% MeOH/CO₂, 80 mL/min, 100 bar).2-6-1

1-((3S)-4-(5-chloro-6-(5- methyl-1H-indazol-4- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one or1-((3R)-4-(5-chloro-6-(5- methyl-1H-indazol-4- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one 2-6/SFC(Phenomenex (S,S)-Whelk-O 1, 250 × 20 mm, 3 μm, 50% MeOH/CO₂ containing20 mM NH₃, 60 g/min, 102 bar) 2-6-2

1-((3R)-4-(5-chloro-6-(5- methyl-1H-indazol-4- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one or1-((3S)-4-(5-chloro-6-(5- methyl-1H-indazol-4- yl)[1,2]thiazolo[3,4-b]pyridin-3-yl)-3-methyl-1- piperazinyl)-2-propen-1-one 2-6/SFC(Phenomenex (S,S)-Whelk-O 1, 250 × 20 mm, 3 μm, 50% MeOH/CO₂ containing20 mM NH₃, 60 g/min, 102 bar) 1-19-1

1-((3S)-4-(5-chloro-7-fluoro- 6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-3-methyl- 1-piperazinyl)-2-propen-1- one 1-19/SFC (IC250 × 30 mm, 5 μm, 50% MeOH/CO₂ (w/20 mM NH₃), 100 g/min, 100 bar).1-19-2

1-((3S)-4-(5-chloro-7-fluoro- 6-(3-hydroxy-1- naphthalenyl)-2,1-benzothiazol-3-yl)-3-methyl- 1-piperazinyl)-2-propen-1- one 1-19/SFC (IC250 × 30 mm, 5 μm, 50% MeOH/CO₂ (w/20 mM NH₃), 100 g/min, 100 bar).3-1-1

1-(4-(5-chloro-7-fluoro-6-(3- hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1- piperazinyl)-2-propen-1-one 3-1/SFC (OD-H 250× 21 mm, 5 μm, 40% MeOH/CO₂ (w/20 mM NH₃), 60 mL/min, 100 bar). 3-1-2

1-(4-(5-chloro-7-fluoro-6-(3- hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-1- piperazinyl)-2-propen-1-one 3-1/SFC (OD-H 250× 21 mm, 5 μm, 40% MeOH/CO₂ (w/20 mM NH₃), 60 mL/min, 100 bar). 8-6-1

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2-(2-propanyl)phenyl)pyrido[2,3- d]pyrimidin-2(1H)-one 8-6/SFC (Chiralpak IC,150 × 30 mm, 5 μm, 30% MeOH/CO₂ (w/20 mM NH₃), 120 g/min, 102 bar).8-6-2

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-4-((2S)-2-methyl-4-(2-propenoyl)- 1-piperazinyl)-1-(2-(2-propanyl)phenyl)pyrido[2,3- d]pyrimidin-2(1H)-one 8-6/SFC (Chiralpak IC,150 × 30 mm, 5 μm, 30% MeOH/CO₂ (w/20 mM NH₃), 120 g/min, 102 bar).8-1-1

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2- propenoyl)-1-piperazinyl)- 2(1H)-quinazolinone8-1/SFC (Chiralpak IC, 300 × 15 mm, 5 μm, 40% MeOH/CO₂ (w/20 mM NH₃),135 g/min, 188 bar). 8-1-2

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-1-(2-(2-propanyl)phenyl)-4-(4-(2- propenoyl)-1-piperazinyl)- 2(1H)-quinazolinone8-1/SFC (Chiralpak IC, 300 × 15 mm, 5 μm, 40% MeOH/CO₂ (w/20 mM NH₃),135 g/min, 188 bar). 8-3-1

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-4-((2S)- 2-methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)-quinazolinone 8-3/SFC (Whelk-01 (S,S), 250 × 21 mm, 5 μm, 30% EtOH/CO₂(w/20 mM NH₃), 70 g/min, 187 bar). 8-3-2

6-chloro-7-(2-fluoro-6- hydroxyphenyl)-4-((2S)- 2-methyl-4-(2-propenoyl)-1- piperazinyl)-1-(2-(2- propanyl)phenyl)-2(1H)-quinazolinone 8-3/SFC (Whelk-01 (S,S), 250 × 21 mm, 5 μm, 30% EtOH/CO₂(w/20 mM NH₃), 70 g/min, 187 bar).

TABLE 12 Analytical Data for General Procedures LRMS: (ESI, +ve Ex. #ion) m/z NMR  1-1 498.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (br s, 1 H),8.04 (s, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 6.81-6.94 (m, 2 H), 6.79 (d, J= 2.9 Hz, 1 H), 6.19 (dd, J = 16.7, 2.2 Hz, 1 H), 5.77 (dd, J = 10.5,2.2 Hz, 1 H), 3.87 (br d, J = 19.5 Hz, 4 H), 3.63 (br t, J = 5.1 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.78 (s, 1 F).  1-2 441.1 ¹H NMR(400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.45-7.53(m, 2H), 7.43 (d, J = 2.4 Hz, 1H), 7.26- 7.35 (m, 2H), 7.10 (d, J = 2.5Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.18 (dd, J = 16.7, 2.3 Hz,1H), 5.76 (d, J = 10.3, 2.4 Hz, 1H), 3.93 (s, 3H), 3.81-3.93 (m, 4H),3.58-3.64 (m, 4H).  1-3 450.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (br. s,1H), 8.18 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.37-7.43 (m,1H), 7.24-7.29 (m, 1H), 7.17-7.23 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H),6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H),5.73-5.79 (m, 1H), 3.82-3.95 (m, 4H), 3.58-3.64 (m, 4H).  1-4 464.0 ¹HNMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H),7.46-7.52 (m, 2H), 7.43 (d, J = 2.4 Hz, 1H), 7.25- 7.36 (m, 2H), 7.10(d, J = 2.5 Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.31 (dd, J =1.9, 16.8 Hz, 1H), 5.74-5.80 (m, 1H), 3.93 (s, 3H), 3.82-3.93 (m, 4H),3.56-3.63 (m, 4H).  1-5 432.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (s, 1H),7.41-7.49 (m, 1H), 7.41 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.80-6.92 (m,2H), 6.18 (dd, J = 16.8, 2.4 Hz, 1H), 5.75 (dd, J = 10.5, 2.3 Hz, 1H),3.79-3.93 (m, 4H), 3.75 (s, 3H), 3.53-3.62 (m, 4H).  1-6 418.0 ¹H NMR(400 MHz, DMSO-d₆) δ 9.98 (br s., 1H), 8.10 (s, 1H), 7.39 (s, 1H),7.20-7.29 (m, 1H), 6.68-6.90 (m, 3H), 6.17 (dd, J = 16.6, 2.4 Hz, 1H),5.75 (dd, J = 10.4, 2.4 Hz, 1H), 3.78-3.93 (m, 4H), 3.53-3.58 (m, 4H). 1-7 498 ¹H NMR (400 MHz, DMSO-d₆) δ 9.79- 10.10 (1 H, m), 8.05-8.12 (1H, m), 7.77- 7.83 (1 H, m), 7.39-7.48 (1 H, m), 7.21- 7.29 (3 H, m),7.04-7.09 (1 H, m), 6.76- 6.91 (1 H, m), 6.14-6.24 (1 H, m), 5.74- 5.81(1 H, m), 5.02-5.30 (1 H, m), 4.08- 4.53 (3 H, m), 3.54-3.81 (6 H, m). 1-8 496 ¹H NMR (400 MHz, DMSO-d₆) δ 9.83- 10.10 (1 H, m), 8.01-8.07 (1H, m), 7.77- 7.84 (1 H, m), 7.39-7.47 (1 H, m), 7.19- 7.31 (3 H, m),7.04-7.10 (1 H, m), 6.80- 6.94 (1 H, m), 6.15-6.28 (1 H, m), 5.75- 5.83(1 H, m), 4.38-4.58 (1 H, m), 4.06- 4.27 (2 H, m), 3.51-3.89 (3 H, m),3.19- 3.29 (1 H, m), 1.58-1.74 (2 H, m), 0.90- 0.99 (3 H, m).  1-9 467.8¹H NMR (400 MHz, DMSO-d₆) δ 9.85- 10.08 (1 H, m), 8.73-8.90 (1 H, m),7.77- 7.83 (1 H, m), 7.72-7.76 (1 H, m), 7.41- 7.47 (1 H, m), 7.21-7.28(3 H, m), 7.04- 7.09 (1 H, m), 6.15-6.23 (2 H, m), 5.67- 5.72 (1 H, m),4.90-5.01 (1 H, m), 4.36- 4.58 (2 H, m), 4.16-4.31 (1 H, m), 1.54- 1.62(3 H, m).  1-10 470 ¹H NMR (400 MHz, DMSO-d₆) δ 13.03- 13.21 (1 H, m),8.05-8.11 (1 H, m), 7.53- 7.63 (2 H, m), 7.35-7.41 (1 H, m), 6.80- 6.99(1 H, m), 6.15-6.28 (1 H, m), 5.74- 5.83 (1 H, m), 4.28-4.55 (2 H, m),4.15- 4.28 (1 H, m), 3.48-3.83 (4 H, m), 2.16- 2.22 (3 H, m), 1.17-1.28(3 H, m).  1-11 512 ¹H NMR (400 MHz, DMSO-d₆) δ 9.83- 10.06 (1 H, m),8.19-8.25 (1 H, m), 7.76- 7.85 (1 H, m), 7.38-7.48 (1 H, m), 7.19- 7.30(3 H, m), 7.03-7.10 (1 H, m), 6.81- 6.95 (1 H, m), 6.15-6.27 (1 H, m),5.74- 5.81 (1 H, m), 4.73-4.88 (1 H, m), 4.36- 4.59 (2 H, m), 4.13-4.26(1 H, m), 4.07- 4.14 (1 H, m), 3.49-3.80 (5 H, m), 1.72- 1.89 (2 H, m). 1-12 511 ¹H NMR (400 MHz, DMSO-d₆) δ 8.26- 8.34 (1 H, m), 8.00-8.09 (2H, m), 7.70- 7.77 (2 H, m), 7.53-7.61 (2 H, m), 7.41- 7.49 (2 H, m),7.32-7.41 (2 H, m), 7.18- 7.25 (1 H, m), 5.15-5.27 (1 H, m), 4.31- 4.56(2 H, m), 3.63-3.91 (2 H, m), 3.42- 3.60 (2 H, m).  1-13 482.0 ¹H NMR(400 MHz, DMSO-d₆) δ 8.13 (d, J = 9.1 Hz, 1H), 8.09 (s, 1H), 7.97 (d, J= 6.8 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.38-7.44 (m, 2H), 7.22 (d, J =8.8 Hz, 1H), 6.87 (dd, J = 16.8, 10.6 Hz, 1H), 6.19 (dd, J = 16.8, 2.4Hz, 1H), 5.77 (dd, J = 10.5, 2.3 Hz, 1H), 3.82-3.94 (m, 4H), 3.87 (s,3H), 3.63-3.69 (m, 4H).  1-14 468.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.91(br. s, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 7.8Hz, 1H), 7.27- 7.38 (m, 3H), 7.15 (d, J = 8.2 Hz, 1H), 6.87 (dd, J =16.6, 10.6 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H), 5.76 (dd, J = 10.5,2.3 Hz, 1H), 3.80-3.95 (m, 4H), 3.60-3.67 (m, 4H).  1-15 497.8 ¹H NMR(400 MHz, DMSO-d₆) δ 8.03- 8.12 (1 H, m), 7.68-7.79 (1 H, m), 7.32- 7.44(1 H, m), 7.11-7.26 (3 H, m), 6.98- 7.06 (1 H, m), 6.77-6.91 (1 H, m),6.13- 6.26 (1 H, m), 5.73-5.83 (1 H, m), 4.08- 4.54 (3 H, m), 3.54-3.80(7 H, m).  1-16 498.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.88- 10.15 (1 H, m),8.08-8.16 (1 H, m), 7.77- 7.83 (1 H, m), 7.40-7.48 (1 H, m), 7.18- 7.30(3 H, m), 7.05-7.10 (1 H, m), 6.80- 6.92 (1 H, m), 6.15-6.24 (1 H, m),5.73- 5.80 (1 H, m), 4.58-4.71 (1 H, m), 4.26- 4.43 (1 H, m), 3.99-4.24(2 H, m), 3.39- 4.00 (6 H, m).  1-17 494.0 ¹H NMR (400 MHz, DMSO-d₆) δ9.81- 10.05 (1 H, m), 8.06-8.12 (1 H, m), 7.77- 7.84 (1 H, m), 7.40-7.47(1 H, m), 7.19- 7.29 (3 H, m), 7.03-7.08 (1 H, m), 6.77- 6.88 (1 H, m),6.19-6.30 (1 H, m), 5.73- 5.82 (1 H, m), 4.73-4.86 (2 H, m), 3.82- 3.96(2 H, m), 3.44-3.52 (2 H, m), 1.88- 2.14 (4 H, m).  1-18 498.0 ¹H NMR(400 MHz, DMSO-d₆) δ 9.85- 10.08 (1 H, m), 8.07-8.13 (1 H, m), 7.77-7.83 (1 H, m), 7.40-7.48 (1 H, m), 7.22- 7.30 (3 H, m), 7.04-7.09 (1 H,m), 6.76- 6.92 (1 H, m), 6.15-6.25 (1 H, m), 5.74- 5.81 (1 H, m),5.04-5.29 (1 H, m), 4.10- 4.52 (3 H, m), 3.53-3.78 (5 H, m).  1-19 482.0¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.90-10.04 (1 H, m), 8.02-8.08 (1 H, m),7.76-7.82 (1 H, m), 7.38-7.46 (1 H, m), 7.20-7.30 (3 H, m), 7.04-7.08 (1H, m), 6.79-6.95 (1 H, m), 6.14-6.27 (1 H, m), 5.73-5.81 (1 H, m),4.38-4.55 (3 H, m), 4.28-4.37 (1 H, m), 4.12-4.26 (1 H, m), 3.46-3.83 (2H, m), 1.15-1.21 (3 H, m)  1-19-1 482.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.83-10.08 (1 H, m), 8.04-8.11 (1 H, m), 7.77-7.84 (1 H, m), 7.38-7.48(1 H, m), 7.19-7.31 (3 H, m), 7.05-7.10 (1 H, m), 6.81-6.98 (1 H, m),6.16-6.28 (1 H, m), 5.75-5.83 (1 H, m), 4.40-4.59 (1 H, m), 4.16-4.40 (1H, m), 3.96-4.07 (1 H, m), 3.48-3.83 (3 H, m), 3.16-3.29 (1 H, m),1.10-1.31 (3 H, m).  1-19-2 482.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.83-10.10 (1 H, m), 8.03-8.10 (1 H, m), 7.77-7.83 (1 H, m), 7.38-7.48(1 H, m), 7.19-7.31 (3 H, m), 7.05-7.10 (1 H, m), 6.81-6.98 (1 H, m),6.15-6.28 (1 H, m), 5.73-5.83 (1 H, m), 4.39-4.56 (2 H, m), 4.15-4.38 (1H, m), 3.97-4.10 (1 H, m), 3.48-3.84 (3 H, m), 1.13-1.27 (3 H, m).  1-20454.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.83- 10.05 (1 H, m), 9.11-9.35 (1 H,m), 8.02- 8.07 (1 H, m), 7.76-7.83 (1 H, m), 7.40- 7.47 (1 H, m),7.20-7.28 (3 H, m), 7.02- 7.09 (1 H, m), 6.33-6.46 (1 H, m), 6.11- 6.22(1 H, m), 5.69-5.78 (1 H, m), 4.69- 4.80 (1 H, m), 4.40-4.49 (1 H, m),4.31- 4.41 (1 H, m), 4.21-4.30 (1 H, m), 3.99- 4.09 (1 H, m).  1-21482.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.85- 10.10 (1 H, m), 8.04-8.09 (1 H,m), 7.77- 7.83 (1 H, m), 7.40-7.47 (1 H, m), 7.19- 7.30 (3 H, m),7.05-7.09 (1 H, m), 6.74- 6.99 (1 H, m), 6.09-6.36 (1 H, m), 5.66- 5.88(1 H, m), 4.39-4.57 (2 H, m), 4.17- 4.39 (1 H, m), 3.96-4.07 (1 H, m),3.48- 3.83 (3 H, m), 1.10-1.29 (3 H, m).  1-22 468.0 ¹H NMR (400 MHz,DMSO-d₆) δ 9.87- 10.03 (1 H, m), 8.45-8.66 (1 H, m), 7.94- 8.01 (1 H,m), 7.76-7.83 (1 H, m), 7.39- 7.47 (1 H, m), 7.21-7.29 (3 H, m), 7.01-7.10 (1 H, m), 6.10-6.25 (2 H, m), 5.59- 5.70 (1 H, m), 4.56-4.68 (1 H,m), 3.99- 4.13 (1 H, m), 3.75-3.87 (2 H, m), 3.55- 3.66 (1 H, m),2.35-2.48 (1 H, m), 2.06- 2.21 (1 H, m).  1-23 482.0 ¹H NMR (400 MHz,DMSO-d₆) δ 9.85- 10.06 (1 H, m), 8.27-8.35 (1 H, m), 7.95- 8.00 (1 H,m), 7.76-7.84 (1 H, m), 7.39- 7.48 (1 H, m), 7.20-7.29 (3 H, m), 7.01-7.10 (1 H, m), 6.23-6.37 (1 H, m), 6.10- 6.20 (1 H, m), 5.58-5.68 (1 H,m), 4.00-4.11 (1 H, m), 3.89-3.99 (1 H, m), 3.67-3.77 (1 H, m),3.35-3.49 (2 H, m), 1.94-2.07 (2 H, m), 1.77-1.90 (1 H, m), 1.62-1.72 (1H, m).  2-7 496.2 ¹H NMR (DMSO-d₆) δ: 9.83-10.11 (m, 1H), 7.90-7.95 (m,1H), 7.76-7.84 (m, 1H), 7.37-7.49 (m, 1H), 7.19-7.31 (m, 3H), 7.06-7.10(m, 1H), 6.86-7.00 (m, 1H), 6.22-6.31 (m, 1H), 5.78-5.86 (m, 1H),4.07-4.22 (m, 3H), 3.89-4.01 (m, 1H), 3.71-3.84 (m, 1H), 3.40-3.52 (m,1H), 1.22-1.34 (m, 6H)  2-8 506.0 ¹H NMR (DMSO-d₆) δ: 13.04-13.25 (m,1H), 8.09-8.15 (m, 1H), 7.55-7.62 (m, 2H), 7.35-7.41 (m, 1H), 6.76-6.94(m, 1H), 6.36-6.62 (m, 1H), 6.16-6.24 (m, 1H), 5.75-5.83 (m, 1H),4.59-4.86 (m, 1H), 4.19-4.58 (m, 1H), 3.52-3.92 (m, 3H), 3.40-3.50 (m,1H), 3.13-3.27 (m, 1H), 2.13-2.21 (m, 3H)  2-9 486.0 ¹H NMR (DMSO-d₆) δ:10.08-10.30 (m, 1H), 7.98-8.07 (m, 1H), 7.29-7.39 (m, 1H), 6.72-6.91 (m,3H), 6.23-6.63 (m, 1H), 6.13-6.24 (m, 1H), 5.74-5.81 (m, 1H), 4.58-4.82(m, 1H), 4.42-4.57 (m, 1H), 4.17-4.38 (m, 1H), 3.52-3.89 (m, 4H)  2-10510.0 ¹H NMR (DMSO-d₆) δ: 9.83-10.06 (m, 1H), 7.93-8.06 (m, 1H),7.75-7.85 (m, 1H), 7.39-7.51 (m, 1H), 7.17-7.32 (m, 3H), 7.00-7.15 (m,1H), 6.76-6.96 (m, 1H), 6.12-6.30 (m, 1H), 5.68-5.86 (m, 1H), 4.59-4.71(m, 1H), 4.35-4.47 (m, 1H), 4.06-4.28 (m, 1H), 3.60-4.06 (m, 3H),3.43-3.58 (m, 1H), 2.08-2.25 (m, 1H), 1.00-1.11 (m, 3H), 0.86-0.97 (m,3H)  1-28 436.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1 H) 8.04 (s, 1 H)7.09-7.24 (m, 1 H) 6.72-6.95 (m, 3 H) 6.12-6.24 (m, 1 H) 5.74-5.77 (m, 1H) 3.83-3.88 (d, 4 H) 3.52-3.72 (m, 4 H)  2-1 451.0 ¹H NMR (400 MHz,DMSO-d₆) δ 9.97 (br. s, 1H), 8.72 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H),7.42 (t, J = 7.1 Hz, 1H), 7.17- 7.28 (m, 3H), 7.09 (d, J = 2.1 Hz, 1H),6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H),5.74-5.79 (m, 1H), 3.81-3.95 (m, 4H), 3.68-3.76 (m, 4H)  2-2 447.0 ¹HNMR (400 MHz, DMSO-d₆) δ 8.58 (d, J = 3.7 Hz, 1H), 7.47-7.55 (m, 1H),7.03 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 6.79-6.93 (m, 1H),6.13-6.24 (m, 1H), 5.77 (dd, J = 10.5, 2.1 Hz, 1H), 4.26-4.54 (m, 2H),3.96-4.25 (m, 1H), 3.65-3.84 (m, 2H), 3.76 (d, J = 2.4 Hz, 3H),3.47-3.64 (m, 2H), 1.19 (s, 3H).  2-3 433.0 ¹H NMR (400 MHz,METHANOL-d₄) δ 8.51 (s, 1H), 7.25-7.34 (m, 1H), 6.74-6.93 (m, 1H),6.65-6.76 (m, 2H), 6.31 (d, J = 16.4 Hz, 1H), 5.84 (dd, J = 10.6, 1.5Hz, 1H), 4.41-4.53 (m, 2H), 4.03-4.15 (m, 1H), 3.54-3.88 (m, 4H), 1.30(d, J = 6.6 Hz, 3H).  2-4 479.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s,1H), 7.93 (d, J = 8.2 Hz, 1H), 7.45-7.53 (m, 2H), 7.26-7.37 (m, 2H),7.19 (d, J = 2.5 Hz, 1H), 6.81-6.95 (m, 1H), 6.15-6.22 (m, 1H), 5.78(dd, J = 10.4, 2.2 Hz, 1H), 4.39-4.58 (m, 2H), 4.16-4.26 (m, 1H), 3.94(s, 3H), 3.68-3.84 (m, 2H), 3.48-3.64 (m, 2H), 1.22 (br. s, 3H).  2-5465.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.66 (s, 1H), 7.79 (d, J= 8.4 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.17-7.30 (m, 3H), 7.09 (d, J =2.4 Hz, 1H), 6.80- 6.94 (m, 1H), 6.14-6.27 (m, 1H), 5.78 (dd, J = 10.6,2.2 Hz, 1H), 3.97-4.57 (m, 3H), 3.48-3.83 (m, 4H), 1.22 (br. s, 3H). 2-6 453.0 ¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br. s, 1H), 8.66 (d, J =2.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 1H),6.80-6.93 (m, 1H), 6.16-6.24 (m, 1H), 5.78 (dd, J = 10.5, 2.3 Hz, 1H),3.97-4.56 (m, 4H), 3.48-3.85 (m, 3H), 2.19 (s, 3H), 1.22 (br s., 3H). 3-1 468.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.90- 10.04 (1H, m), 8.10 (1H,s), 7.80 (1H, d, J = 8.41 Hz), 7.43 (1H, ddd, J = 1.96, 6.11, 8.17 Hz),7.16-7.31 (3H, m), 7.07 (1H, d, J = 2.35 Hz), 6.87 (1H, dd, J = 10.47,16.73 Hz), 6.19 (1H, dd, J = 2.25, 16.73 Hz), 5.77 (1H, dd, J = 2.25,10.47 Hz), 3.88 (4H, br d, J = 19.56 Hz), 3.61- 3.72 (4H, m). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −123.78 (s, 1F).  3-2 469 ¹H NMR (400 MHz, CDCl₃) δ9.43 (br. s., 1 H) 8.12 (d, J = 15.1 Hz, 1 H) 7.77 (d, J = 9.6 Hz, 1 H)7.66 (d, J= 7.6 Hz, 1 H) 7.59 (d, J = 8.0 Hz, 1 H) 7.45 (s, 1 H)7.21-7.26 (m, 1 H) 7.03 (br d, J = 10.4 Hz, 1 H) 6.95 (d, J = 15.1 Hz, 1H) 6.71 (d, J = 9.6 Hz, 1 H) 3.93-4.14 (m, 4 H) 3.52-3.59 (m, 4 H). ¹⁹FNMR (376 MHz, CDCl₃) δ −123.91 (s, 1 F).  3-3 453.0 ¹H NMR (400 MHz,DMSO-d₆) δ 8.82- 8.88 (1 H, m), 8.52-8.63 (1 H, m), 8.09- 8.22 (2 H, m),7.89-8.02 (2 H, m), 7.67- 7.74 (1 H, m), 6.80-6.96 (1 H, m), 6.13- 6.25(1 H, m), 5.72-5.84 (1 H, m), 3.77- 4.03 (4 H, m), 3.56-3.74 (4 H, m). 3-4 469.0 H NMR (400 MHz, DMSO-d₆) δ 11.81- 12.11 (1 H, m), 8.05-8.15(1 H, m), 7.58- 7.67 (1 H, m), 7.42-7.49 (1 H, m), 7.35- 7.42 (1 H, m),7.14-7.20 (1 H, m), 6.80- 6.93 (1 H, m), 6.44-6.53 (1 H, m), 6.14- 6.24(1 H, m), 5.72-5.82 (1 H, m), 3.80- 3.95 (4 H, m), 3.61-3.69 (4 H, m). 3-5 456.0 ¹H NMR (400 MHz, DMSO-d₆) δ 12.99- 13.26 (1 H, m), 8.10-8.14(1 H, m), 7.54- 7.60 (2 H, m), 7.33-7.40 (1 H, m), 6.81- 6.94 (1 H, m),6.14-6.25 (1 H, m), 5.74- 5.80 (1 H, m), 3.81-3.95 (4 H, m), 3.62- 3.71(4 H, m), 2.12-2.20 (3 H, m).  3-6 436.0 ¹H NMR (400 MHz, METHANOL-d₄) δ7.84 (d, J = 1.17 Hz, 1H), 7.26 (dt, J = 6.75, 8.27 Hz, 1H), 6.71-6.90(m, 2H), 6.62-6.71 (m, 1H), 6.25 (dd, J = 1.96, 16.82 Hz, 1H), 5.79 (dd,J = 1.86, 10.66 Hz, 1H), 3.91-4.03 (m, 4H), 3.57-3.71 (m, 4H), 3.33 (s,1H). ¹⁹F NMR (377 MHz, METHANOL-d₄) δ −116.77 (1 F, s), −125.66 (1 F, d,J = 2.6 Hz)  3-7 438.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1 H),7.53-7.62 (m, 1 H), 7.47 (td, J = 9.7, 2.5 Hz, 1 H), 7.28 (td, J = 8.5,2.2 Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.18 (dd, J = 16.7, 2.2Hz, 1 H), 5.71- 5.79 (m, 1 H), 3.86 (br d, J = 19.6 Hz, 4 H), 3.63 (t, J= 5.2 Hz, 4 H)  3-8 432.2 ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1 H),8.02 (s, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.77 (dd, J = 8.2, 2.5 Hz, 1 H), 6.58 (d, J = 2.5 Hz, 1 H), 6.18(dd, J = 16.6, 2.3 Hz, 1 H), 5.72-5.80 (m, 1 H), 3.77-3.93 (m, 4 H),3.62 (t, J = 5.1 Hz, 4 H), 1.94 (s, 3 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−124.66 (s, 1 F)  3-9 467.8 ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 1 H)7.54 (d, J = 8.8 Hz, 1 H) 7.10 (dd, J = 8.8, 3.1 Hz, 1 H) 7.02-7.07 (m,1 H) 6.85 (dd, J = 16.7, 10.5 Hz, 1 H) 6.18 (dd, J = 16.7, 2.2 Hz, 1 H)5.72-5.79 (m, 1 H) 3.86 (br d, J = 19.4 Hz, 4 H) 3.79 (s, 3 H) 3.62 (t,J = 5.1 Hz, 4 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.83 (s, 1 F)  3-10454.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1 H), 8.05 (s, 1 H), 7.39(dd, J = 11.0, 9.6 Hz, 1 H), 6.97 (dd, J = 9.5, 7.1 Hz, 1 H), 6.85 (dd,J = 16.6, 10.4 Hz, 1 H), 6.17 (dd, J = 16.6, 2.2 Hz, 1 H), 5.75 (dd, J =10.5, 2.2 Hz, 1 H), 3.76-3.95 (m, 4 H), 3.62 (br t, J = 5.1 Hz, 4 H).¹⁹F NMR (376 MHz, DMSO-d₆) δ −122.67 (br s, 1 F), −123.60 (d, J = 4.3Hz, 1 F), −130.52 (d, J = 2.6 Hz, 1 F)  3-11 453.8 ¹H NMR (400 MHz,DMSO-d₆) δ 9.83- 10.02 (1 H, m), 8.04 (1 H, s), 7.40 (1 H, br d, J = 8.6Hz), 6.76-7.03 (3 H, m), 6.12-6.22 (1 H, m), 5.69-5.82 (1 H, m), 3.86 (4H, br d, J = 18.6 Hz), 3.63 (4 H, br d, J = 4.7 Hz). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −124.09 (s, 1 F)  3-12 431.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.00(s, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.85 (dd, J = 16.6, 10.4 Hz, 1 H),6.57 (dd, J = 8.0, 2.0 Hz, 1 H), 6.39 (d, J = 1.8 Hz, 1 H), 6.18 (dd, J= 16.7, 2.2 Hz, 1 H), 5.69- 5.85 (m, 1 H), 4.99 (s, 2 H), 3.86 (br d, J= 19.6 Hz, 4 H), 3.56-3.70 (m, 4 H), 1.88 (s, 3 H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −124.75 (1 F, s)  3-13 473.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.98(s, 1 H), 8.05 (s, 1 H), 7.54 (br d, J = 8.4 Hz, 1 H), 7.49 (s, 1 H),7.29 (d, J = 8.4 Hz, 1 H), 6.85 (dd, J = 16.5, 10.5 Hz, 1 H), 6.18 (dd,J = 16.6, 2.0 Hz, 1 H), 5.76 (dd, J = 10.5, 2.1 Hz, 1H), 3.86 (br d, J =19.8 Hz, 4 H), 3.63 (br t, J = 4.9 Hz, 4 H), 2.03 (s, 3 H), 2.01 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.58 (s, 1 F)  3-14 435.0 ¹H NMR(400 MHz, DMSO-d₆) δ 8.03 (s, 1 H), 7.01 (t, J = 9.2 Hz, 1 H), 6.85 (dd,J = 16.7, 10.5 Hz, 1 H), 6.62-6.71 (m, 1 H), 6.52 (dd, J = 6.1, 2.7 Hz,1 H), 6.18 (dd, J = 16.7, 2.2 Hz, 1 H), 5.70- 5.81 (m, 1 H), 5.11 (s, 2H), 3.86 (br d, J = 19.6 Hz, 4 H), 3.52-3.69 (m, 4 H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −123.91 (s, 1 F), −131.17 (s, 1 F)  3-15 453.0 ¹H NMR (400MHz, DMSO-d₆) δ 8.06 (s, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.63(ddd, J = 13.0, 6.6, 2.5 Hz, 1 H), 6.33 (br d, J = 2.0 Hz, 1 H), 6.18(dd, J = 16.6, 2.3 Hz, 1 H), 5.71-5.82 (m, 1 H), 5.44 (s, 2 H),3.76-3.96 (m, 4 H), 3.56- 3.71 (m, 4 H)  3-16 453.9 ¹H NMR (400 MHz,DMSO-d₆) δ 10.12 (s, 1 H), 8.08 (s, 1 H), 6.92 (ddd, J = 12.3, 6.5, 2.9Hz, 1 H), 6.85 (dd, J = 16.6, 10.4 Hz, 1 H), 6.58-6.65 (m, 1 H), 6.18(dd, J = 16.7, 2.2 Hz, 1 H), 5.72- 5.79 (m, 1 H), 3.78-3.92 (m, 4 H),3.63 (t, J = 5.2 Hz, 4 H)  3-17 486.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.86(br s, 1 H), 8.05 (s, 1 H), 7.68 (s, 1 H), 6.96 (s, 1 H), 6.85 (dd, J =16.6, 10.4 Hz, 1 H), 6.18 (dd, J = 16.6, 2.3 Hz, 1 H), 5.76 (dd, J =10.5, 2.2 Hz, 1 H), 3.78- 3.93 (m, 4 H), 3.56-3.68 (m, 4 H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −123.87 (s, 1 F)  3-18 469.9 ¹H NMR (400 MHz,DMSO-d₆) δ 10.36- 10.69 (m, 1 H), 8.04 (s, 1 H), 7.55 (d, J = 11.0 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.18(dd, J = 16.7, 2.2 Hz, 1 H), 5.70-5.80 (m, 1 H), 3.86 (br d, J = 19.8Hz, 4 H), 3.62 (br t, J = 5.1 Hz, 4 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−123.82 (s, 1 F), −132.61 (br s, 1 F)  3-19 451.0 ¹H NMR (400 MHz,DMSO-d₆) δ 8.01 (s, 1 H), 7.20 (d, J = 8.6 Hz, 1 H), 6.85 (dd, J = 16.7,10.5 Hz, 1 H), 6.66 (dd, J = 8.6, 2.7 Hz, 1 H), 6.54 (d, J = 2.5 Hz, 1H), 6.17 (dd, J = 16.7, 2.2 Hz, 1 H), 5.67- 5.82 (m, 1 H), 5.40 (s, 2H), 3.85 (br d, J = 19.4 Hz, 4 H), 3.54-3.73 (m, 4 H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −124.25 (1 F, s)  3-20 485.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.04(s, 1 H), 7.50 (s, 1 H), 6.85 (dd, J = 16.7, 10.5 Hz, 1 H), 6.79 (s, 1H), 6.18 (dd, J = 16.7, 1.9 Hz, 1 H), 5.76 (dd, J = 10.6, 1.8 Hz, 1 H),5.70 (s, 2 H), 3.86 (br d, J = 19.8 Hz, 4 H), 3.63 (br d, J = 4.9 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.05 (br s, 1 F)  3-21 445.2 ¹H NMR(400 MHz, DMSO-d₆) δ 8.54 (d, J = 5.4 Hz, 1 H), 8.29 (s, 1 H), 8.02 (s,1 H), 7.47 (d, J = 5.2 Hz, 1 H), 6.78 (dd, J = 16.7, 10.5 Hz, 1 H), 6.10(dd, J = 16.7, 2.2 Hz, 1 H), 5.62-5.75 (m, 1 H), 3.71-3.88 (m, 4 H),3.56 (br t, J = 5.3 Hz, 4 H), 2.49-2.64 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.04 (1F, s)  3-22 486.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (br s, 1 H), 8.07(s, 1 H), 7.14 (d, J = 2.7 Hz, 1 H), 6.78-6.93 (m, 2 H), 6.19 (dd, J =16.7, 2.2 Hz, 1 H), 5.70-5.82 (m, 1 H), 3.79-3.92 (m, 4 H), 3.63 (br t,J = 5.0 Hz, 4 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.13 (s, 1 F)  3-23452.1 ¹H NMR (400 MHz, DMSO-d₆) δ 8.03- 8.14 (m, 3 H) 7.41-7.69 (m, 5 H)6.84- 6.91 (m, 1 H) 6.17-6.22 (m, 1 H) 5.76- 5.79 (m, 1 H) 3.86-3.91 (m,4 H) 3.65- 3.67 (m, 4 H)  3-24 453 ¹H NMR (400 MHz, DMSO-d₆) δ 8.78-8.87 (m, 1 H) 8.43-8.54 (m, 1 H) 8.04- 8.40 (m, 2 H) 7.45-7.79 (m, 2 H)7.53- 7.65 (m, 1 H) 6.74-6.98 (m, 1 H) 6.09- 6.26 (m, 1 H) 5.79-5.81 (m,1 H) 3.83- 3.93 (m, 4 H) 3.52-3.66 (m, 4 H)  3-25 442 ¹H NMR (400 MHz,DMSO-d₆) δ 8.03 (s, 1 H) 6.81-6.98 (m, 4 H) 6.15-6.20 (m, 1 H) 5.72-5.86(m, 3 H) 3.83-3.88 (m, 4 H) 3.6-3.62 (m, 4 H)  4-1 480.0 ¹H NMR (400MHz, DMSO-d₆) δ 9.82- 10.04 (1 H, m), 7.79 (1 H, d, J = 8.2 Hz), 7.66 (1H, s), 7.43 (1 H, dt, J = 8.3, 4.0 Hz), 7.26 (1 H, d, J = 2.3 Hz), 7.22(2 H, d, J = 3.7 Hz), 7.05 (1 H, d, J = 2.3 Hz), 6.26-6.38 (1 H, m),6.12 (1 H, dd, J = 16.8, 2.2 Hz), 5.66-5.72 (1 H, m), 4.58- 4.67 (4 H,m), 4.50 (2 H, s), 4.22 (2 H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.98(1 F, s)  4-2 418.0 ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (1 H, d, J = 1.4Hz), 6.25-6.36 (1 H, m), 6.10 (1 H, dd, J = 17.0, 2.3 Hz), 5.64- 5.72 (1H, m), 4.58 (4 H, s), 4.47 (2 H, s), 4.18 (2 H, s). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −113.54 (1 F, s)  4-3 494.0 ¹H NMR (400 MHz, DMSO-d₆) δ 7.93(1 H, d, J = 8.4 Hz), 7.67 (1 H, s), 7.45- 7.57 (2 H, m), 7.23-7.36 (2H, m), 7.16 (1 H, d, J = 2.5 Hz), 6.27-6.39 (1 H, m), 6.11 (1 H, dd, J =17.0, 2.2 Hz), 5.65- 5.76 (1 H, m), 4.58-4.67 (4 H, m), 4.50 (2 H, s),4.22 (2 H, s), 3.93 (3 H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.88 (1 F,s)  4-4 391.8 ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (1 H, br s), 7.63-7.77 (1H, m), 6.04-6.33 (2 H, m), 5.60-5.77 (1 H, m), 4.89 (1 H, br d, J = 3.3Hz), 4.72 (2 H, br dd, J = 8.1, 3.6 Hz), 4.28 (2 H, br dd, J = 8.0, 3.9Hz). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −113.24 (1 F, s)  4-5 468.0 ¹H NMR(400 MHz, DMSO-d6) δ 8.92- 9.00 (1 H, m), 7.93 (1 H, d, J = 8.2 Hz),7.72 (1 H, s), 7.45-7.60 (2 H, m), 7.25- 7.36 (2 H, m), 7.17 (1 H, d, J= 2.3 Hz), 6.08-6.36 (2 H, m), 5.69 (1 H, dd, J = 9.8, 2.2 Hz),4.87-5.01 (1 H, m), 4.69- 4.84 (2 H, m), 4.33 (2 H, br d, J = 3.3 Hz),3.94 (3 H, s). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.93 (1 F, s)  4-6 454.0¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (1 H, s), 8.97 (1 H, d, J = 7.0 Hz),7.80 (1 H, d, J = 8.2 Hz), 7.72 (1 H, s), 7.39- 7.49 (1 H, m), 7.16-7.32(3 H, m), 7.05 (1 H, d, J = 2.2 Hz), 6.08-6.36 (2 H, m), 5.65-5.73 (1 H,m), 4.87-5.05 (1 H, m), 4.77 (2 H, td, J = 8.2, 2.6 Hz), 4.33 (2 H, brt, J = 6.2 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.03 (1 F, s)  4-7 391.8¹H NMR (400 MHz, DMSO-d₆) δ 9.23- 9.42 (1 H, m), 8.04 (1 H, d, J = 1.0Hz), 6.37 (1 H, dd, J = 17.0, 10.2 Hz), 6.15 (1 H, dd, J = 17.0, 2.0Hz), 5.65-5.86 (1 H, m), 4.70 (1 H, br t, J = 8.0 Hz), 4.35- 4.48 (1 H,m), 4.25-4.33 (1 H, m), 4.22 (1 H, br dd, J = 9.0, 4.3 Hz), 3.99 (1 H,br dd, J = 10.3, 4.4 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.81 (1 F, s) 4-8 420.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (1 H, br s), 8.15 (1 H, brd, J = 8.8 Hz), 6.58- 6.97 (1 H, m), 5.97-6.27 (1 H, m), 5.58- 5.74 (1H, m), 4.50 (1 H, br d, J = 11.5 Hz), 3.91 (1 H, br d, J = 13.5 Hz),3.14- 3.28 (2 H, m), 2.85-2.97 (1 H, m), 2.08- 2.23 (1 H, m), 1.79-1.91(1 H, m), 1.64- 1.78 (1 H, m), 1.45-1.60 (1 H, m). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −114.17 (1 F, br s)  4-9 482.0 ¹H NMR (400 MHz, DMSO-d₆) δ9.87- 10.07 (1 H, m), 8.50-8.70 (1 H, m), 8.06- 8.23 (1 H, m), 7.70-7.88(1 H, m), 7.39- 7.48 (1 H, m), 7.19-7.28 (3 H, m), 7.02- 7.08 (1 H, m),6.68-6.93 (1 H, m), 6.05- 6.23 (1 H, m), 5.64-5.78 (1 H, m), 4.51- 4.63(1 H, m), 4.06-4.17 (1 H, m), 3.91- 4.04 (1 H, m), 3.14-3.30 (1 H, m),2.91- 3.01 (1 H, m), 2.14-2.29 (1 H, m), 1.83- 1.96 (1 H, m), 1.68-1.82(1 H, m), 1.49- 1.65 (1 H, m).  5-1 468.0 ¹H NMR (400 MHz, DMSO-d₆) δ9.89- 10.10 (m, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.73 (s, 1 H), 7.43(ddd, J = 8.2, 5.1, 2.9 Hz, 1 H), 7.20-7.30 (m, 3 H), 7.05 (d, J = 2.2Hz, 1 H), 6.81 (dd, J = 16.7, 10.5 Hz, 1 H), 6.10-6.23 (m, 1 H),5.69-5.81 (m, 1 H), 5.37-5.59 (m, 1 H), 4.63-4.74 (m, 3 H), 4.53-4.61(m, 1 H), 3.14-3.23 (m, 3 H). ¹⁹F NMR (376 MHz, DMSO- d₆) δ −124.10 (1F, s)  5-2 468.2 ¹H NMR (400 MHz, DMSO-d₆) δ 9.89- 10.09 (m, 1 H), 8.70(s, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.69 (s, 1 H), 7.39-7.46 (m, 1 H),7.16-7.31 (m, 3 H), 7.05 (d, J = 2.2 Hz, 1 H), 6.20-6.32 (m, 1 H), 6.08-6.18 (m, 1 H), 5.65 (dd, J = 10.1, 1.9 Hz, 1 H), 4.57 (dd, J = 8.1, 1.9Hz, 2 H), 4.40 (br d, J = 8.4 Hz, 2 H), 1.67 (s, 3 H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −124.13 (1 F, s)  5-3 484.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.95(s, 1 H), 8.74 (s, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.70 (s, 1 H), 7.42(br t, J = 6.6 Hz, 1 H), 7.16-7.28 (m, 3 H), 7.05 (d, J = 2.2 Hz, 1 H),6.23-6.41 (m, 1 H), 6.07- 6.19 (m, 1 H), 5.66 (dd, J = 10.1, 1.7 Hz, 1H), 5.36 (br t, J = 5.8 Hz, 1 H), 4.49 (s, 4 H), 3.74 (br d, J = 5.5 Hz,2 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.12 (1 F, s)  5-4 482.1 ¹H NMR(400 MHz, DMSO-d₆) δ 9.99 (s, 1 H), 8.02 (s, 1 H), 7.80 (d, J = 8.1 Hz,1 H), 7.38-7.52 (m, 1 H), 7.16-7.34 (m, 3 H), 7.07 (s, 1 H), 6.75-6.96(m, 1 H), 6.11-6.35 (m, 1 H), 5.66-5.90 (m, 1 H), 4.43-4.91 (m, 1 H),4.07-4.39 (m, 1 H), 3.90-4.05 (m, 1 H), 3.71-3.87 (m, 1 H), 3.61 (br d,J = 9.7 Hz, 1 H), 3.33-3.51 (m, 2 H), 1.36 (br s, 3 H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −124.10 (1 F, s)  5-5 480.1 ¹H NMR (400 MHz, DMSO-d₆) δ9.97 (s, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 4.4 Hz, 1 H),7.38-7.49 (m, 1 H), 7.16- 7.29 (m, 3 H), 7.05 (d, J = 1.0 Hz, 1 H),6.54-6.86 (m, 1 H), 6.14-6.31 (m, 1 H), 5.74-5.80 (m, 1 H), 5.21-5.40(m, 1 H), 4.96-5.17 (m, 1 H), 4.61-4.73 (m, 1 H), 4.15-4.42 (m, 2 H),3.55-3.92 (m, 1 H), 2.25-2.47 (m, 1 H), 1.93-2.20 (m, 1 H)  5-6 480.1 ¹HNMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.69(d, J = 4.1 Hz, 1 H), 7.43 (dt, J = 8.1, 4.1 Hz, 1 H), 7.26 (d, J = 2.3Hz, 1 H), 7.19- 7.25 (m, 2 H), 7.05 (d, J = 2.1 Hz, 1 H), 6.55-6.83 (m,1 H), 6.23 (ddd, J = 16.5, 7.5, 2.2 Hz, 1 H), 5.79 (br d, J = 2.1 Hz, 1H), 5.22-5.40 (m, 1 H), 4.96-5.18 (m, 1 H), 4.61-4.72 (m, 1 H),4.18-4.44 (m, 2 H), 3.57-3.94 (m, 1 H), 2.27-2.45 (m, 1 H), 1.92-2.24(m, 1 H)  5-7 482.1 ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (1 H, br s), 8.02(1 H, s), 7.80 (1 H, d, J = 8.5 Hz), 7.35-7.53 (1 H, m), 7.17-7.33 (3 H,m), 7.07 (1 H, d, J = 2.3 Hz), 6.84 (1 H, dd, J = 16.7, 10.5 Hz), 6.19(1 H, dd, J = 16.8, 1.7 Hz), 5.68-5.83 (1 H, m), 4.43-4.93 (1 H, m),4.08-4.39 (1 H, m), 3.93-4.05 (1 H, m), 3.79 (1 H, br d, J = 11.6 Hz),3.54-3.66 (1 H, m), 3.37- 3.50 (2 H, m), 1.35 (3 H, br s). ¹⁹F NMR (376MHz, DMSO-d₆) δ −123.81 (1 F, d, J = 16.5 Hz)  5-8 480.0 ¹H NMR (400MHz, DMSO-d₆) δ 9.98 (s, 1 H), 7.86 (br d, J = 8.7 Hz, 1 H), 7.80 (d, J= 8.1 Hz, 1 H), 7.37-7.53 (m, 1 H), 7.19-7.31 (m, 3 H), 7.06 (br s, 1H), 6.25- 6.55 (m, 1 H), 6.11-6.24 (m, 1 H), 5.64- 5.82 (m, 1 H),5.14-5.44 (m, 1 H), 5.03- 5.12 (m, 1 H), 4.24-4.59 (m, 1 H), 3.63- 4.20(m, 3 H), 2.22-2.48 (m, 2 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−124.17-−123.93 (m, 1 F)  5-9 468.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s,1 H), 8.04 (s, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.38-7.52 (m, 1 H),7.15-7.35 (m, 3 H), 7.07 (d, J = 2.3 Hz, 1 H), 6.39 (dd, J = 17.0, 10.4Hz, 1 H), 6.16 (dd, J = 17.0, 2.1 Hz, 1 H), 5.66-5.81 (m, 1 H), 4.94-5.06 (m, 1 H), 4.67 (br t, J = 8.7 Hz, 1 H), 4.49 (br dd, J = 9.4, 5.3Hz, 1 H), 4.31-4.43 (m, 1 H), 4.21 (br dd, J = 10.6, 5.2 Hz, 1 H), 3.43(s, 3 H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.00 (s, 1 F)  6-1 452.0 ¹HNMR (400 MHz, DMSO-ds) δ 7.97- 8.10 (m, 1 H), 7.60 (d, J = 8.9 Hz, 1 H),6.86 (dd, J = 16.6, 10.6 Hz, 1 H), 6.57 (d, J = 8.9 Hz, 1 H), 6.38 (s, 2H), 6.19 (dd, J = 16.8, 2.3 Hz, 1 H), 5.71-5.84 (m, 1 H), 3.86 (br d, J= 19.9 Hz, 4 H), 3.63 (br d, J = 1.0 Hz, 4 H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −126.04 (1 F, s)  6-2 437.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.67-8.79 (1 H, m), 8.18 (1 H, dd, J = 8.3, 1.0 Hz), 8.10 (1 H, s), 7.61 (1H, dd, J = 8.2, 4.7 Hz), 6.86 (1 H, dd, J = 16.6, 10.4 Hz), 6.19 (1 H,dd, J = 16.8, 2.3 Hz), 5.77 (1 H, dd, J = 10.4, 2.3 Hz), 3.79- 3.97 (4H, m), 3.58-3.73 (4 H, m). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −125.75 (1 F, s) 7-1 518.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (br. s., 1 H) 8.12 (d, J =2.2 Hz, 1 H) 7.80 (d, J = 8.2 Hz, 1 H) 7.43 (br t, J = 7.0 Hz, 1 H)7.20-7.30 (m, 3 H) 7.08 (dd, J = 5.8, 2.2 Hz, 1 H) 6.78-6.91 (m, 1 H)6.27- 6.70 (m, 1 H) 6.20 (dd, J = 16.6, 2.0 Hz, 1 H) 5.76-5.84 (m, 1 H)4.73-4.87 (m, 1 H) 4.19-4.72 (m, 2 H) 3.55-3.90 (m, 3 H) 3.36-3.47 (m, 1H)  7-2 500.0 ¹H NMR (DMSO-d₆) δ: 9.73-10.17 (m, 1H), 8.04-8.12 (m, 1H),7.77-7.84 (m, 1H), 7.39-7.48 (m, 1H), 7.20-7.30 (m, 3H), 7.06-7.10 (m,1H), 6.77-6.93 (m, 1H), 6.15-6.24 (m, 1H), 5.74-5.83 (m, 1H), 4.57-4.92(m, 3H), 4.14-4.54 (m, 2H), 3.55-3.87 (m, 3H), 3.21-3.29 (m, 1H)  7-3526.0 ¹H NMR (DMSO-d₆) δ: 9.76-10.22 (m, 1H), 8.09-8.14 (m, 1H),7.77-7.84 (m, 1H), 7.39-7.48 (m, 1H), 7.20-7.29 (m, 3H), 7.04-7.11 (m,1H), 6.82 (br. s., 1H), 6.14-6.22 (m, 1H), 5.77-5.83 (m, 1H), 3.68-5.36(m, 4H), 3.60-3.67 (m, 3H)  8-1 547 ¹H NMR (400 MHz, DMSO-d₆) δ 10.06(br. d, J = 15.1 Hz, 1 H) 8.03 (d, J = 1.2 Hz, 1 H) 7.51-7.56 (m, 1 H)7.45 (t, J = 7.6 Hz, 1 H) 7.33 (tdd, J = 7.5, 7.5, 3.8, 1.4 Hz, 1 H)7.14-7.25 (m, 2 H) 6.84 (dd, J = 16.8, 10.4 Hz, 1 H) 6.62-6.74 (m, 2 H)6.14-6.26 (m, 2 H) 5.71-5.78 (m, 1 H) 3.71-3.99 (m, 8 H) 2.52-2.59 (m, 1H) 1.02-1.12 (m, 6 H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ −113.6 (s, 1 F)−114.8 (s, 1 F).  8-2 548.2 ¹H NMR (400 MHz, CDCl₃) δ 8.61 (1 H, br s)8.17 (1 H, s) 7.49-7.55 (2 H, m) 7.35-7.43 (1 H, m) 7.23-7.30 (1 H, m)7.09 (1 H, d, J = 7.88 Hz) 6.58-6.72 (3 H, m) 6.41 (1 H, dd, J = 16.79,1.66 Hz) 5.82 (1 H, dd, J = 10.47, 1.55 Hz) 3.80- 4.15 (8 H, m) 2.71 (1H, spt, J = 6.84 Hz) 1.23 (3 H, d, J = 6.84 Hz) 1.03 (4 H, d, J = 6.84Hz)  8-3 561 ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1 H) 7.35-7.49 (m, 2 H)7.18-7.32 (m, 1 H) 7.01-7.17 (m, 2 H) 6.67-6.74 (m, 1 H) 6.48-6.65 (m, 3H) 6.32-6.44 (m, 1 H) 5.77-5.83 (m, 1 H) 4.19-5.14 (m, 3 H) 3.75-3.98(m, 1 H) 3.41-3.68 (m, 2 H) 2.85-3.28 (m, 1 H) 2.49-2.71 (m, 1 H)1.34-1.54 (m, 3 H) 1.13-1.21 (m, 3 H) 1.00-1.07 (m, 3 H). ¹⁹F NMR (377MHz, CDCl₃) δ −113.43-−113.3 (m, 1 F) −114.3-−113.9 (m, 1 F).  8-3-1561.2 ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1 H) 7.37-7.51 (m, 2 H)7.21-7.34 (m, 1 H) 7.05-7.20 (m, 2 H) 6.70 (br d, J = 8.1 Hz, 1 H)6.52-6.67 (m, 3 H) 6.39 (dd, J = 16.8, 1.7 Hz, 1 H) 5.80 (dd, J = 10.5,1.6 Hz, 1 H) 4.26-5.00 (m, 3 H) 3.40- 4.00 (m, 3 H) 3.06-3.24 (m, 1 H)2.52- 2.69 (m, 1 H) 1.20 (d, J = 6.2 Hz, 6 H) 1.04 (br d, J = 6.4 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ −113.31 (br d, J = 63.3 Hz, 1 F) −113.99(br d, J = 33.8 Hz, 1 F).  8-3-2 561.2 ¹H NMR (400 MHz, CDCl₃) δ 7.79(br s, 1 H) 7.35-7.48 (m, 2 H) 7.21-7.32 (m, 1 H) 7.04-7.17 (m, 2 H)6.68 (d, J = 8.3 Hz, 1 H) 6.49-6.66 (m, 3 H) 6.36 (br d, J = 16.6 Hz, 1H) 5.78 (dd, J = 10.4, 1.9 Hz, 1 H) 4.29-5.11 (m, 2 H) 3.46-4.02 (m, 3H) 2.93-3.29 (m, 2 H) 2.49-2.68 (m, 1 H) 1.48 (dd, J = 14.5, 2.1 Hz, 6H) 1.03 (br d, J = 6.0 Hz, 3 H). ¹⁹F NMR (377 MHz, CDCl₃) δ −113.32 (brd, J = 9.5 Hz, 1 F) −114.02-−113.78 (m, 1 F).  8-4 576 ¹H NMR (400 MHz,CDCl₃) δ 8.58 (s, 1 H) 8.13 (s, 1 H) 7.41-7.50 (m, 1 H) 7.32 (s, 1 H)7.30 (s, 1 H) 7.22-7.30 (m, 1 H) 6.53-6.75 (m, 3 H) 6.42 (dd, J = 16.8,1.7 Hz, 1 H) 5.77-5.86 (m, 1 H) 3.53- 5.25 (m, 6 H) 2.98-3.34 (m, 1 H)2.16- 2.49 (m, 4 H) 1.52 (br d, J = 19.5 Hz, 3 H) 1.07-1.17 (m, 6 H).¹⁹F NMR (377 MHz, CDCl₃) δ −104.8 (br. s., 1 F) −104.9 (br. s., 1 F). 8-5 546.2 ¹H NMR (400 MHz, DMSO-d₆) δ 10.08-10.10 (m, 1 H) 8.47-8.48(m, 1 H) 8.37 (s, 1H), 8.05 (s, 1H), 7.16-7.26 (m, 1H) 7.04-7.25 (m, 1H) 6.82-6.90 (m, 1 H) 6.63-6.77 (m, 2 H) 6.30-6.31 (m, 1 H) 6.16-6.21(m, 1 H) 5.72-5.79 (m, 1 H) 3.84-4.02 (m, 6 H) 3.76-3.81 (m, 2 H),1.54-1.55 (m, 1 H) 1.23 (s, 2H) 0.74-0.85 (m, 1 H), 0.52-0.69 (m, 1 H) 8-6 562.1 ¹H NMR (400 MHz, CDCl₃) δ 8.62 (1 H, br s) 8.10-8.13 (1 H, m)7.49-7.56 (2 H, m) 7.35-7.43 (1 H, m) 7.22-7.30 (1 H, m) 7.10 (1 H, brs) 6.54-6.73 (3 H, m) 6.38-6.45 (1 H, m) 5.82 (1 H, dd, J = 10.57, 1.45Hz) 2.60-5.27 (8 H, m) 1.42- 1.54 (3 H, m) 1.23 (3 H, d, J = 6.84 Hz)1.03 (3 H, d, J = 6.84 Hz)  9-1 611.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.42(br d, J = 17.0 Hz, 1 H), 7.86-8.11 (m, 1 H), 7.50-7.63 (m, 1 H), 7.47(br t, J = 6.0 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.15-7.26 (m, 1 H),7.05 (d, J = 2.3 Hz, 1 H), 6.78-6.96 (m, 1 H), 6.44-6.58 (m, 1 H),6.11-6.29 (m, 2 H), 5.71-5.82 (m, 1 H), 4.68-4.98 (m, 1 H), 3.96-4.52(m, 3 H), 3.52-3.85 (m, 2 H), 3.34-3.51 (m, 1 H), 2.95-3.26 (m, 1 H),1.27-1.41 (m, 3 H), 0.95-1.13 (m, 6 H)  9-2 531.0 ¹H NMR (400 MHz,DMSO-d₆) δ 7.91- 8.08 (m, 1 H), 7.49-7.67 (m, 2 H), 7.41 (br d, J = 5.8Hz, 1 H), 7.21 (br s, 1 H), 6.76-6.98 (m, 1 H), 6.52-6.67 (m, 1 H),6.09-6.29 (m, 1 H), 5.75 (br s, 1 H), 4.61- 4.96 (m, 1 H), 4.23-4.48 (m,1 H), 3.93- 4.21 (m, 2 H), 3.50-3.77 (m, 1H), 3.33- 3.49 (m, 1 H),3.23-3.28 (m, 1 H), 2.94- 3.24 (m, 1 H), 1.27 (br d, J = 9.3 Hz, 6 H),1.09 (br s, 3 H)  9-3 576.2 ¹H NMR (400 MHz, DMSO-d₆) δ 7.88- 8.01 (m, 1H), 7.49-7.61 (m, 1 H), 7.46 (br t, J = 7.6 Hz, 1 H), 7.36 (t, J = 7.3Hz, 1 H), 7.15-7.25 (m, 1 H), 7.08 (d, J = 8.7 Hz, 1 H), 6.76-6.95 (m, 1H), 6.57 (dd, J = 8.7, 2.5 Hz, 1 H), 6.17-6.32 (m, 2 H), 6.11-6.16 (m, 1H), 5.72-5.81 (m, 1 H), 5.40 (br d, J = 10.8 Hz, 2 H), 4.66- 4.99 (m, 1H), 4.21-4.52 (m, 2 H), 3.94- 4.20 (m, 2 H), 3.53-3.82 (m, 2 H), 3.36-3.51 (m, 1 H), 1.27-1.40 (m, 3 H), 0.95- 1.12 (m, 6 H)  9-4 593.2 ¹H NMR(400 MHz, DMSO-d₆) δ 9.94 (br. s, 1H), 8.10 (s, 1H), 7.72 (d, J = 8.1Hz, 1H), 7.43-7.51 (m, 1H), 7.31-7.42 (m, 3H), 7.11-7.27 (m, 4H),6.68-6.93 (m, 2H), 6.14-6.36 (m, 2H), 5.70-5.83 (m, 1H), 3.72-4.12 (m,8H), 2.23-2.40 (m, 1H), 1.32-1.65 (m, 2H), 0.95-1.16 (m, 3H), 0.36-0.75(m, 3H).  9-5 530.2 ¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (s, 1 H) 7.85-7.90(m, 2 H) 7.64- 7.72 (m, 2 H) 7.10-7.18 (m, 1 H) 6.73- 6.78 (m, 1 H)6.57-6.67 (m, 2 H) 6.33 (s, 1 H) 6.10-6.14 (m, 1 H) 5.66-5.72 (m, 1 H)3.85-3.96 (m, 4 H) 3.48-3.79 (m, 2 H) 3.68-3.75 (m, 2 H)  9-6 546.2 ¹HNMR (400 MHz, DMSO-d₆) δ 9.92-10.25 (m, 1 H) 8.44-8.82 (m, 1 H)8.27-8.40 (m, 1 H) 7.99 (s, 1 H) 7.27-7.28 (m, 1 H) 7.11-7.21 (m, 1 H)6.72-6.91 (m, 1 H) 6.48-6.71 (m, 2 H) 6.03-6.31 (m, 2 H) 5.48-5.79 (m, 1H) 3.57 4.16 (m, 8 H) 1.36-1.70 (m, 1 H) 0.21-0.92 (m, 4 H)  9-7 561.2¹H NMR (400 MHz, METHANOL-d₄) δ 8.44-8.56 (m, 1 H) 8.41-8.44 (m, 1 H)8.00-8.03 (m, 1 H) 7.35-7.37 (m, 1 H) 7.14-7.23 (m, 1 H) 6.75-6.83 (m, 1H), 6.56-6.66 (m, 2 H) 6.40-6.46 (m, 1 H) 6.25-6.31 (m, 1 H) 5.75-5.82(m, 1 H) 4.42-4.67 (m, 2 H) 3.59-3.89 (m, 2 H) 1.57-1.70 (m, 1 H)1.45-1.52 (m, 3 H) 1.27 (s, 4H) 0.80-0.88 (m, 3 H)  9-8 561.2 ¹H NMR(400 MHz, METHANOL-d₄) δ 8.43-8.50 (m, 1 H) 8.30-8.36 (m, 1 H) 7.91-7.97(m, 1 H) 7.25-7.32 (m, 1 H) 7.07-7.14 (m, 1 H) 6.70-6.78 (m, 1 H)6.47-6.60 (m, 2 H) 6.33-6.41 (m, 1 H) 6.16-6.26 (m, 1 H) 5.68-5.77 (m, 1H) 4.32-4.52 (m, 2 H) 3.50-3.81 (m, 2 H) 1.51-1.62 (m, 1 H) 1.36-1.41(m, 3 H) 1.19 (s, 4 H) 0.74-0.85 (m, 3 H)  9-9 581.2 ¹H NMR (400 MHz,METHANOL-d₄) δ 8.48-8.57 (m, 1 H) 8.31-8.41 (m, 1 H) 8.13-8.18 (m, 1 H)7.38-7.54 (m, 3 H) 7.28-7.40 (m, 1 H) 6.82-6.95 (m, 1 H) 6.45-6.50 (m, 1H) 6.28-6.38 (m, 1 H) 5.81-5.90 (m, 1 H) 4.47-4.63 (m, 2 H) 4.07-4.25(m, 1 H) 3.63-3.94 (m, 2 H) 2.13-2.21 (m, 3 H) 1.62-1.75 (m, 1 H)1.51-1.57 (m, 3 H) 1.27-1.37 (m, 3 H) 0.86-0.95 (m, 3 H)  9-10 597.2 ¹HNMR (400 MHz, DMSO-d₆) δ 8.01 (br d, J = 18.0 Hz, 1 H), 7.71 (d, J = 8.1Hz, 1 H), 7.50-7.58 (m, 1 H), 7.39-7.49 (m, 2 H), 7.35 (t, J = 7.4 Hz, 1H), 7.09- 7.27 (m, 2 H), 6.78-6.97 (m, 1 H), 6.14- 6.29 (m, 2 H),5.71-5.82 (m, 1 H), 4.70- 4.98 (m, 1 H), 3.98-4.54 (m, 3 H), 3.39- 3.85(m, 2 H), 2.91-3.29 (m, 1 H), 1.27- 1.41 (m, 3 H), 1.10 (br t, J = 6.2Hz, 3 H), 0.94-1.07 (m, 3 H)  9-11 561.2 ¹H NMR (400 MHz, DMSO-d₆) δ7.99 (br d, J = 16.6 Hz, 1 H), 7.49-7.68 (m, 2 H), 7.29-7.48 (m, 4 H),7.10-7.26 (m, 2 H), 6.76-6.96 (m, 1 H), 6.12-6.31 (m, 2 H), 5.71-5.82(m, 1 H), 4.68-4.97 (m, 1 H), 3.95-4.51 (m, 3 H), 3.44-3.85 (m, 2 H),2.92-3.26 (m, 2 H), 1.27-1.41 (m, 3 H), 1.06-1.17 (m, 3 H), 0.92-1.06(m, 3 H)  9-12 583 ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1 H) 8.08 (d, J =8.3 Hz, 1 H) 7.51-7.59 (m, 1 H) 7.34-7.44 (m, 3 H) 7.21 (td, J = 7.7,0.8 Hz, 1 H) 6.85 (d, J = 8.5 Hz, 1 H) 6.56-6.75 (m, 1 H) 6.45 (dd, J =16.8, 1.7 Hz, 1 H) 5.81-5.90 (m, 1 H) 4.33-5.25 (m, 3 H) 3.82-4.01 (m, 1H) 3.05-3.71 (m, 3 H) 2.40-2.58 (m, 2 H) 2.20-2.37 (m, 2 H) 1.57 (br d,J = 18.0 Hz, 3 H) 1.10 (td, J = 7.6, 0.8 Hz, 6 H).  9-13 579.2 ¹H NMR(400 MHz, CDCl₃) δ 7.93 (0.5 H, s) 7.92 (0.5 H, s) 7.69-7.74 (1 H, m)7.18-7.51 (7 H, m) 7.11-7.16 (1 H, m) 6.88 (1 H, dd, J = 25.82, 2.54 Hz)6.59- 6.68 (2 H, m) 6.42 (1 H, dd, J = 16.82, 1.76 Hz) 5.82 (1 H, dd, J= 10.56, 1.56 Hz) 3.81-4.11 (8 H, m) 2.65-2.74 (1 H, m) 1.25 (1.5 H, d,J = 6.85 Hz) 1.22 (1.5 H, d, J = 6.85 Hz) 1.13 (1.5 H, d, J = 6.85 Hz)0.98 (1.5 H, d, J = 6.85 Hz)  9-14 540.2 ¹H NMR (400 MHz, DMSO-d₆) δ10.21 (0.6 H, br s) 10.12 (0.4 H, br s) 8.29- 8.35 (1 H, m) 7.28-7.38 (1H, m) 6.73- 6.85 (3 H, m) 6.17 (1 H, dd, J = 16.59, 2.28 Hz) 5.74 (1 H,dd, J = 10.37, 2.28 Hz) 5.30-5.38 (0.6 H, m) 5.00-5.06 (0.4 H, m)3.61-3.96 (8 H, m) 2.90- 3.06 (1 H, m) 1.69-1.83 (1 H, m) 1.15- 1.52 (6H, m) 0.69-1.04 (6 H, m) 10-1 503.1 ¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (1H, br s) 8.33 (1 H, s) 7.36-7.45 (2 H, m) 7.24-7.36 (4 H, m) 6.90 (1 H,dd, J = 16.63, 10.37 Hz) 6.70-6.80 (2 H, m) 6.18 (1 H, dd, J = 16.73,2.25 Hz) 5.75 (1 H, dd, J = 10.56, 2.15 Hz) 3.83-3.97 (4 H, m) 3.47-3.62(4 H, m) 1.98-2.06 (3 H, m) 10-2 519.2 ¹H NMR (CDCl₃) δ: 8.16-8.24 (m,1H), 7.61-7.67 (m, 1H), 7.43-7.52 (m, 2H), 7.15-7.23 (m, 1H), 7.05-7.13(m, 1H), 6.92-7.02 (m, 1H), 6.70-6.82 (m, 2H), 6.57-6.69 (m, 1H),6.30-6.40 (m, 1H), 5.68-5.81 (m, 1H), 3.81-4.03 (m, 4H), 3.49-3.71 (m,7H), 2.52-2.66 (m, 1H). 10-3 537.0 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.35(1 H, s) 7.38-7.42 (1 H, m) 7.37 (1 H, s) 7.31-7.36 (2 H, m) 7.21 (1 H,td, J = 8.31, 6.85 Hz) 6.83 (1 H, dd, J = 16.73, 10.66 Hz) 6.69 (1 H, d,J = 8.41 Hz) 6.63 (1 H, br t, J = 8.80 Hz) 6.24 (1 H, dd, J = 16.82,1.96 Hz) 5.77 (1 H, dd, J = 10.66, 1.86 Hz) 3.94-4.01 (4 H, m) 3.58-3.66(4 H, m) 1.99-2.04 (3 H, m) 10-4 531.2 ¹H NMR (400 MHz, METHANOL-d₄) δ8.34 (1 H, s) 7.44-7.51 (2 H, m) 7.34 (1 H, d, J = 4.30 Hz) 7.27-7.32 (1H, m) 7.15-7.25 (2 H, m) 6.83 (1 H, dd, J = 16.82, 10.56 Hz) 6.66 (1 H,d, J = 8.22 Hz) 6.57-6.64 (1 H, m) 6.21-6.27 (1 H, m) 5.77 (1 H, dd, J =10.66, 1.86 Hz) 3.93-4.02 (4 H, m) 3.56-3.65 (4 H, m) 2.46-2.56 (1 H, m)0.98-1.13 (6 H, m) 10-5 517.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.44 (1 H,s) 7.46-7.57 (3 H, m) 7.26- 7.44 (3 H, m) 6.94 (1 H, dd, J = 16.73,10.66 Hz) 6.77 (1 H, d, J = 8.22 Hz) 6.68- 6.75 (1 H, m) 6.35 (1 H, dd,J = 16.73, 1.86 Hz) 5.88 (1 H, dd, J = 10.76, 1.96 Hz) 4.04-4.12 (4 H,m) 3.67-3.76 (4 H, m) 2.36-2.60 (2 H, m) 1.06 (3 H, q, J = 7.63 Hz) 10-6504.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.56 (1 H, br d, J = 5.09 Hz) 8.51(1 H, s) 8.42 (1 H, s) 7.49 (1 H, br d, J = 5.09 Hz) 7.43 (1 H, s)7.22-7.29 (1 H, m) 6.87 (1 H, dd, J = 16.73, 10.66 Hz) 6.72 (1 H, br d,J = 8.41 Hz) 6.67 (1 H, br t, J = 8.71 Hz) 6.28 (1 H, dd, J = 16.73,1.27 Hz) 5.79-5.84 (1 H, m) 3.98-4.06 (4 H, m) 3.64-3.73 (4 H, m) 2.19(3 H, s) 10-7 517.2 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.46 (1 H, s)7.24-7.41 (5 H, m) 6.93 (1 H, dd, J = 16.82, 10.56 Hz) 6.76 (1 H, d, J =8.41 Hz) 6.68-6.74 (1 H, m) 6.34 (1 H, dd, J = 16.82, 1.96 Hz) 5.87 (1H, dd, J = 10.56, 1.96 Hz) 4.05-4.11 (4 H, m) 3.68-3.76 (4 H, m) 2.02 (3H, s) 2.00 (3 H, s) 10-8 504.2 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.62 (1H, dd, J = 4.89, 1.56 Hz) 8.43 (1 H, s) 7.87 (1 H, dd, J = 7.73, 1.47Hz) 7.48 (1 H, dd, J = 7.63, 5.09 Hz) 7.43 (1 H, s) 7.27 (1 H, td, J =8.31, 6.85 Hz) 6.89 (1 H, dd, J = 16.82, 10.56 Hz) 6.74 (1 H, d, J =8.22 Hz) 6.68 (1 H, t, J = 8.80 Hz) 6.30 (1 H, dd, J = 16.73, 1.86 Hz)5.83 (1 H, dd, J = 10.66, 1.86 Hz) 3.99-4.07 (4 H, m) 3.65-3.74 (4 H, m)2.34 (3 H, s) 10-9 528.2 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.33 (1 H, s)7.75 (1 H, s) 7.52-7.56 (1 H, m) 7.12-7.28 (4 H, m) 6.82 (1 H, dd, J =16.73, 10.66 Hz) 6.64 (1 H, d, J = 8.41 Hz) 6.55-6.61 (1 H, m) 6.24 (1H, dd, J = 16.82, 1.96 Hz) 6.14 (1 H, dd, J = 3.33, 0.78 Hz) 5.77 (1 H,dd, J = 10.56, 1.96 Hz) 3.91-4.01 (4 H, m) 3.55-3.63 (4 H, m) 10-10529.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.52 (1 H, s) 7.55-7.63 (2 H, m)7.44- 7.51 (2 H, m) 7.35-7.43 (1 H, m) 7.24 (1 H, t, J = 7.04 Hz) 7.02(1 H, dd, J = 16.73, 10.66 Hz) 6.83-6.90 (1 H, m) 6.76-6.83 (1 H, m)6.43 (1 H, dd, J = 16.73, 1.66 Hz) 5.97 (1 H, dd, J = 10.66, 1.66 Hz)4.13-4.19 (4 H, m) 3.76-3.82 (4 H, m) 1.56-1.70 (1 H, m) 0.70-0.92 (3 H,m) 0.55-0.68 (1 H, m) 10-11 523.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.40(1 H, s) 7.50-7.70 (4 H, m) 7.42 (1 H, s) 7.22-7.30 (1 H, m) 6.89 (1 H,dd, J = 16.73, 10.66 Hz) 6.63-6.76 (2 H, m) 6.30 (1 H, dd, J = 16.73,1.86 Hz) 5.83 (1 H, dd, J = 10.56, 1.96 Hz) 3.98-4.10 (4 H, m) 3.62-3.76(4 H, m) 10-12 543.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.45 (1 H, s)7.63-7.67 (1 H, m) 7.51- 7.54 (1 H, m) 7.44-7.48 (1 H, m) 7.34- 7.37 (1H, m) 7.21 (1 H, td, J = 8.22, 6.85 Hz) 6.90 (1 H, dd, J = 16.73, 10.66Hz) 6.58-6.72 (2 H, m) 6.31 (1 H, dd, J = 16.82, 1.96 Hz) 5.84 (1 H, dd,J = 10.56, 1.96 Hz) 4.03-4.08 (4 H, m) 3.69-3.75 (4 H, m) 2.22 (1.25 H,s) 2.20 (1.75 H, s) 10-13 447.0 ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (1 H,br s) 8.31 (1 H, s) 8.14 (1 H, s) 7.31- 7.40 (1 H, m) 6.78-6.92 (3 H, m)6.17 (1 H, dd, J = 16.63, 2.35 Hz) 5.74 (1 H, dd, J = 10.37, 2.35 Hz)3.79-3.92 (4 H, m) 3.46-3.55 (4 H, m) 11-1-1 567.2 ¹H NMR (400 MHz,CDCl₃) δ 10.28 (1 H, br s) 7.94 (1 H, s) 7.35-7.49 (4 H, m) 7.25-7.31 (2H, m) 7.11 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J = 16.79, 10.57 Hz)6.54 (1 H, s) 6.41 (1 H, dd, J = 16.79, 1.87 Hz) 5.81 (1 H, dd, J =10.57, 1.66 Hz) 3.83-4.07 (8 H, m) 2.74 (1 H, spt, J = 6.84 Hz) 2.13 (3H, s) 1.23 (3 H, d, J = 6.84 Hz) 1.04 (3 H, d, J = 6.84 Hz) 11-1-2 567.2¹H NMR (400 MHz, CDCl₃) δ 10.37 (1 H, br s) 7.94 (1 H, s) 7.34-7.50 (4H, m) 7.21-7.31 (2 H, m) 7.13 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J =16.90, 10.68 Hz) 6.55 (1 H, s) 6.41 (1 H, dd, J = 16.79, 1.66 Hz) 5.81(1 H, dd, J = 10.47, 1.55 Hz) 3.83-4.08 (8 H, m) 2.70 (1 H, spt, J =6.84 Hz) 2.13 (3 H, s) 1.22 (3 H, d, J = 6.84 Hz) 1.03 (3 H, d, J = 6.84Hz). MS (ESI, +ve) m/z: 567.2 [M + H]⁺. 11-2-1 581.3 ¹H NMR (400 MHz,METHANOL-d₄) δ 8.12-8.21 (m, 1H), 7.30-7.56 (m, 6H), 7.21 (d, J = 7.7Hz, 1H), 6.80-6.97 (m, 1H), 6.46 (s, 1H), 6.30-6.41 (m, 1H), 5.79-5.94(m, 1H), 5.02-5.14 (m, 1H), 4.39-4.69 (m, 2H), 4.07-4.30 (m, 1H), 3.67(s, 2H), 3.21-3.51 (m, 1H), 2.68-2.84 (m, 1H), 2.13 (s, 3H), 1.54 (br d,J = 6.0 Hz, 3H), 1.23 (d, J = 7.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H)11-2-2 581.2 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.15 (s, 1H), 7.42-7.58 (m,4H), 7.30-7.39 (m, 2H), 7.25 (d, J = 7.7 Hz, 1H), 6.81- 6.98 (m, 1H),6.48 (s, 1H), 6.29-6.41 (m, 1H), 5.87 (dd, J = 1.35, 10.68 Hz, 1H),5.02-5.12 (m, 1H), 4.42-4.69 (m, 2H), 4.05-4.29 (m, 1H), 3.65-3.93 (m,2H), 3.21-3.47 (m, 1H), 2.64-2.79 (m, 1H), 2.15 (s, 3H), 1.53 (br d, J =6.6 Hz, 3H), 1.23 (br d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H)

TABLE 13 Analytical Data for Individual Examples LRMS: (ESI, +ve Ex. #ion) m/z NMR 12 453.2 ¹H NMR (CDCl₃) δ: 8.30-8.37 (m, 1H), 8.11-8.18 (m,1H), 7.29-7.38 (m, 1H), 6.96-7.18 (m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85(m, 1H), 6.59-6.72 (m, 1H), 6.31-6.42 (m, 1H), 5.73-5.84 (m, 1H),3.73-4.05 (m, 4H), 3.35-3.62 (m, 4H), 2.40-2.52 (m, 1H), 1.35-1.42 (m,1H), 1.29-1.34 (m, 1H), 1.03-1.14 (m, 2H). m/z (ESI) M + H: 453.2. 13504.2 ¹H NMR (CDCl₃) δ: 7.96-8.09 (m, 2H), 7.46-7.57 (m, 2H), 7.37-7.44(m, 1H), 7.29-7.33 (m, 1H), 7.20-7.26 (m, 1H), 6.96-7.07 (m, 1H),6.81-6.87 (m, 1H), 6.70-6.77 (m, 1H), 6.54-6.67 (m, 1H), 6.29-6.41 (m,1H), 5.68-5.82 (m, 1H), 3.74-3.96 (m, 4H), 3.12-3.43 (m, 4H). 14 481.2.¹H NMR (CDCl₃) δ: 8.10-8.22 (m, 2H), 7.29-7.38 (m, 1H), 6.86-6.93 (m,1H), 6.77-6.85 (m, 1H), 6.61-6.72 (m, 1H), 6.33-6.44 (m, 1H), 5.74-5.85(m, 1H), 3.82-4.05 (m, 4H), 3.75-3.82 (m, 1H), 3.40-3.63 (m, 4H),2.06-2.24 (m, 4H), 1.81-1.96 (m, 2H), 1.67-1.79 (m, 2H). 15 496.2 ¹H NMR(CDCl₃) δ: 8.08-8.15 (m, 1H), 7.98-8.05 (m, 1H), 7.29-7.39 (m, 1H),6.86-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.70 (m, 1H), 6.30-6.43 (m,1H), 5.72-5.84 (m, 1H), 3.77-4.05 (m, 4H), 3.40-3.56 (m, 4H), 3.32-3.38(m, 4H), 1.73-1.85 (m, 4H), 1.64-1.70 (m, 2H) 16 505.2 ¹H NMR (CDCl₃) δ:8.41-8.45 (m, 1H), 8.17-8.20 (m, 1H), 7.40-7.45 (m, 2H), 7.28-7.37 (m,2H), 7.20-7.26 (m, 1H), 6.78-6.87 (m, 2H), 6.59-6.70 (m, 1H), 6.31-6.41(m, 1H), 5.97-6.06 (m, 1H), 5.74-5.81 (m, 1H), 3.76-4.03 (m, 4H),3.38-3.53 (m, 4H). 17-1 539.2 ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H),8.10 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.40-7.46 (m, 1H), 7.19-7.30 (m,3H), 7.97 (d, J = 2.4 Hz, 1H), 6.62-6.71 (m, 2H), 3.80-3.93 (m, 4H),3.62-3.69 (m, 4H), 3.07 (d, J = 4.1 Hz, 2H), 2.17 (s, 6H). 17-2 525.0 ¹HNMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.40-7.46 (m, 1H), 7.19-7.30 (m, 3H), 7.97 (d, J = 2.4 Hz, 1H),6.62-6.71 (m, 2H), 3.80-3.93 (m, 4H), 3.62-3.69 (m, 4H), 3.07 (d, J =4.1 Hz, 2H), 2.17 (s, 6H). 18-1 512.0 ¹H NMR (400 MHz, DMSO-d₆) δ 8.12(s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.47-7.55 (m, 2H), 7.25-7.34 (m, 2H),7.19 (d, J = 2.5 Hz, 1H), 5.43 (br. s, 1H), 5.20 (br. s, 1H), 5.14 (t, J= 5.8 Hz, 1H), 4.12 (d, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.78-3.85 (m,4H), 3.54-3.66 (m, 4H). 18-2 560.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (br.s, 1H), 8.13 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.40-7.47 (m, 1H),7.19-7.29 (m, 3H), 7.07 (d, J = 2.4 Hz, 1H), 5.41 (s, 1H), 4.38 (s, 1H),4.38 (s, 2H), 3.84-3.93 (m, 4H), 3.62-3.72 (m, 4H). 18-3 498.0 ¹H NMR(400 MHz, DMSO-d₆) δ 9.98 (br. s, 1H), 8.11 (s, 1H), 7.79 (d, J = 8.2Hz, 1H), 7.37-7.48 (m, 1H), 7.17-7.28 (m, 3H), 7.07 (d, J = 2.4 Hz, 1H),5.43 (br. s, 1H), 5.20 (br. s, 1H), 5.07-5.14 (m, 1H), 4.12 (br. s, 2H),3.78-3.86 (m, 4H), 3.57-3.66 (m, 4H). 19-1 486.0 ¹H NMR (400 MHz,DMSO-d₆) δ 8.13 (s, 1H), 8.02 (s, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.99(d, J = 2.4 Hz, 1H), 6.85 (dd, J = 16.6, 10.6 Hz, 1H), 6.18 (dd, J =16.7, 2.3 Hz, 1H), 5.76 (dd, J = 10.5, 2.3 Hz, 1H), 3.85-3.95 (m, 4H),3.84 (s, 3H), 3.62-3.72 (m, 4H), 3.56 (s, 3H). 19-2 472.0 ¹H NMR (400MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.12 (d, J =2.2 Hz, 1H), 6.81-6.91 (m, 2H), 6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.76(dd, J = 10.4, 2.4 Hz, 1H), 3.81-3.94 (m, 4H), 3.62-3.70 (m, 4H), 3.52(s, 3H). 19-3 472.0 ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.11 (s,1H), 8.01 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.77-6.90 (m, 2H), 6.18(dd, J = 16.7, 2.5 Hz, 1H), 5.76 (dd, J = 10.4, 2.2 Hz, 1H), 4.03 (s,3H), 3.80-3.94 (m, 4H), 3.58-3.66 (m, 4H). 20 512 ¹H NMR (400 MHz,DMSO-d₆) δ 9.93 (br s, 1H), 8.11 (s, 1H), 7.80 (d, J = 12 Hz, 1H), 7.43(m, 1H), 7.26-7.20 (m, 3H), 7.07 (s, 1H), 5.32 (s, 1H), 5.16 (s, 1H),3.83 (br s, 4H), 3.63 (br s, 4H), 3.53 (t, J = 8.0 Hz, 2H), 2.42 (t, J =8.0 Hz, 2H). ¹⁹FNMR (377 MHz, DMSO-d₆) δ −123.8 (s, 1F). 21 469 ¹H NMR(400 MHz, CDCl₃) δ 8.81 (dd, J = 4.2, 1.3 Hz, 1 H) 7.72-7.78 (m, 2 H)7.64 (s, 1 H) 7.28 (d, J = 2.2 Hz, 1 H) 7.16 (dd, J = 8.4, 4.3 Hz, 1 H)6.56-6.66 (m, 1 H) 6.40 (dd, J = 16.8, 1.6 Hz, 1 H) 5.78-5.87 (m, 1 H)4.01 (br. s, 2 H) 3.89 (br. s, 2 H) 3.50-3.60 (m, 4 H). ¹⁹F NMR (376MHz, CDCl₃) δ −121.33 (s, 1 F). 22 512.0 ¹H NMR (400 MHz, DMSO-d₆) δ3.14- 3.28 (m, 1 H) 3.52-3.87 (m, 3 H) 4.15- 5.03 (m, 2 H) 5.15-5.23 (m,1 H) 5.77- 5.83 (m, 1 H) 6.13-6.24 (m, 1 H) 6.86 (br. s, 1 H) 7.06-7.12(m, 1 H) 7.20- 7.30 (m, 3 H) 7.38-7.49 (m, 1 H) 7.76- 7.84 (m, 1 H)8.07-8.13 (m, 1 H) 9.98 (br. s, 1 H) 13.42 (br. s, 1 H). 23 482.0 ¹H NMR(400 MHz, DMSO-d₆) δ 12.92- 13.19 (1 H, m), 8.02-8.21 (1 H, m), 7.47-7.60 (2 H, m), 7.02-7.09 (1 H, m), 6.80- 6.93 (1 H, m), 6.15-6.25 (1 H,m), 5.71- 5.82 (1 H, m), 3.80-3.96 (4 H, m), 3.60- 3.72 (4 H, m),1.55-1.74 (1 H, m), 0.72- 0.79 (2 H, m), 0.58-0.71 (2 H, m). 24 482.0 ¹HNMR (400 MHz, METHANOL-d₄) δ 7.90 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H),7.43 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.05 (t, J = 7.4 Hz,1H), 6.72- 6.84 (m, 1H), 6.67 (s, 1H), 6.15-6.28 (m, 1H), 5.68-5.81 (m,1H), 3.87-3.97 (m, 4H), 3.63 (m, 4H), 2.90 (s, 3H). 25 468.0 ¹H NMR (400MHz, METHANOL-d₄) δ 7.85 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.39 (t, J =7.6 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.82(s, 1H), 6.71 (dd, J = 10.8, 16.8 Hz, 1H), 6.2 (dd, J = 1.5, 16.8 Hz,1H), 5.70 (dd, J = 1.5, 10.8 Hz, 1H), 3.82-3.93 (m, 4H), 3.50-3.66 (m,4H) 26 468.0 ¹H NMR (400 MHz, METHANOL-d₄) δ 7.90 (s, 1H), 7.53 (d, J =8.2 Hz, 1H), 7.42-7.49 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.03-7.08 (m,J = 7.6 Hz, 1H), 6.67- 6.81 (m, 2H), 6.19 (dd, J = 1.8, 16.6 Hz, 1H),5.72 (dd, J = 1.8, 10.6 Hz, 1H), 3.87-3.93 (m, 4H), 3.56-3.66 (m, 4H).27 512.3 ¹H NMR (400 MHz, CDCl₃) δ 9.51 (0.6 H, br s) 8.98 (0.4 H, br s)7.63 (0.4 H, s) 7.58 (0.6 H, s) 7.35-7.43 (2 H, m) 7.10- 7.26 (3 H, m)6.78 (1 H, dd, J = 16.63, 8.22 Hz) 6.59-6.71 (2 H, m) 6.36 (1 H, dd, J =16.82, 1.57 Hz) 5.78 (1 H, dd, J = 10.56, 1.37 Hz) 4.10-4.38 (4 H, m)3.80- 4.03 (4 H, m) 2.60-2.72 (1 H, m) 2.61 (1.2 H, s) 2.59 (1.8 H, s)0.91-1.08 (6 H, m) 28 517.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (1 H,s) 8.15 (0.33 H, s) 8.10 (0.67 H, s) 7.19-7.31 (5 H, m) 7.10-7.16 (1 H,m) 6.86 (1 H, dd, J = 16.73, 10.66 Hz) 6.62-6.78 (2 H, m) 6.27 (1 H, dd,J = 16.82, 1.96 Hz) 5.80 (1 H, dd, J = 10.66, 1.86 Hz) 4.94-5.01 (1 H,m) 3.93-4.03 (4 H, m) 3.49-3.60 (4 H, m) 1.81 (3 H, d, J = 7.04 Hz) 29521.1 ¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (1 H, s) 8.19 (1 H, s)7.26-7.34 (3 H, m) 6.98 (2 H, t, J = 8.71 Hz) 6.69- 6.91 (3 H, m) 6.28(1 H, dd, J = 16.92, 1.86 Hz) 5.82 (1 H, dd, J = 10.56, 1.76 Hz)4.54-4.65 (2 H, m) 3.99 (4 H, m) 3.58 (4 H, m) 30 489.0 ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.21 (1 H, s) 8.06 (1 H, s) 7.62-7.69 (2 H, m) 7.45-7.51(3 H, m) 7.24-7.32 (1 H, m) 6.81-6.90 (1 H, m) 6.75 (1 H, t, J = 8.41Hz) 6.65 (1 H, dd, J = 16.82, 10.56 Hz) 6.38 (1 H, dd, J = 16.82, 1.76Hz) 5.79 (1 H, dd, J = 10.56, 1.76 Hz) 3.86-4.02 (4 H, m) 3.57-3.76 (4H, m) 31 489.1 ¹H NMR (400 MHz, CDCl₃) δ 8.15 (1 H, s) 8.12 (1 H, s)7.68-7.73 (2 H, m) 7.53- 7.58 (3 H, m) 7.30 (1 H, br td, J = 8.22, 6.65Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.78 (1 H, t, J = 8.61 Hz) 6.57 (1 H, dd,J = 16.82, 10.56 Hz) 6.28 (1 H, dd, J = 16.73, 1.66 Hz) 5.71 (1 H, dd, J= 10.56, 1.56 Hz) 3.78-3.89 (4 H, m) 3.51-3.73 (4 H, m) 32 443.1 ¹H NMR(400 MHz, CDCl₃) δ 8.23 (1 H, s) 8.11 (1 H, s) 7.32 (1 H, td, J = 8.31,6.46 Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.77- 6.83 (1 H, m) 6.65 (1 H, dd, J= 16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd, J =10.47, 1.86 Hz) 4.18 (3 H, s) 3.79-4.05 (4 H, m) 3.34- 3.54 (4 H, m) 33443.1 ¹H NMR (400 MHz, CDCl₃) δ 8.32 (1 H, s) 8.01 (1 H, s) 7.32 (1 H,td, J = 8.27, 6.55 Hz) 6.89 (1 H, d, J = 8.22 Hz) 6.77- 6.83 (1 H, m)6.60 (1 H, dd, J = 17.02, 10.56 Hz) 6.30 (1 H, dd, J = 16.82, 1.76 Hz)5.75 (1 H, dd, J = 10.56, 1.76 Hz) 4.22 (3 H, s) 3.67-3.98 (4 H, m)3.25- 3.55 (4 H, m) 34 427.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.13 (1 H, s)8.12 (1 H, s) 7.28-7.36 (4 H, m) 7.20-7.26 (1 H, m) 6.65 (1 H, dd, J =16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.57 Hz) 5.78 (1 H, dd, J =10.56, 1.56 Hz) 4.61 (2 H, s) 3.83-4.01 (4 H, m) 3.48-3.62 (4 H, m). 35503.1 ¹H NMR (400 MHz, CDCl₃) δ 8.13 (1 H, s) 8.11 (1 H, s) 7.12-7.37 (6H, m) 6.91 (1 H, d, J = 8.22 Hz) 6.77 (1 H, t, J = 8.61 Hz) 6.64 (1 H,dd, J = 16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H,dd, J = 10.56, 1.96 Hz) 4.55 (2 H, s) 3.34-4.01 (8 H, m) 36 503.1 ¹H NMR(400 MHz, CDCl₃) δ 8.12 (1 H, s) 8.05 (1 H, s) 7.26-7.36 (5 H, m) 7.19-7.24 (1 H, m) 6.93 (1 H, d, J = 8.41 Hz) 6.76 (1 H, t, J = 8.31 Hz) 6.58(1 H, dd, J = 16.82, 10.76 Hz) 6.28 (1 H, dd, J = 16.82, 1.76 Hz) 5.75(1 H, dd, J = 10.56, 1.76 Hz) 4.54 (2 H, s) 3.32-3.93 (8 H, m) 37 523 ¹HNMR (400 MHz, CDCl₃) δ 8.23 (0.6 H, s) 8.22 (0.4 H, s) 8.02 (0.4 H, s)8.00 (0.6 H, s) 7.19-7.57 (8 H, m) 6.68 (0.4 H, dd, J = 16.82, 10.56 Hz)6.60 (0.6 H, dd, J = 16.82, 10.56 Hz) 6.38 (0.4 H, dd, J = 16.63, 1.76Hz) 6.32 (0.6 H, dd, J = 16.82, 1.76 Hz) 5.79 (0.4 H, dd, J = 10.56,1.76 Hz) 5.73 (0.6 H, dd, J = 10.56, 1.76 Hz) 4.67 (1.2 H, s) 4.60 (0.8H, s) 3.74-4.06 (4 H, m) 3.46-3.70 (4 H, m) 2.21 (1.8 H, s) 2.06 (1.2 H,s) 38 483.3 ¹H NMR (400 MHz, CDCl₃) δ 8.04 (1 H, s) 7.26-7.33 (1 H, m)6.82 (1 H, d, J = 8.29 Hz) 6.71 (1 H, t, J = 8.91 Hz) 6.51 (1 H, dd, J =16.79, 10.57 Hz) 6.30 (1 H, dd, J = 16.79, 1.45 Hz) 5.72 (1 H, dd, J =10.47, 1.55 Hz) 4.15 (2 H, br d, J = 6.43 Hz) 3.69-3.90 (8 H, m)1.14-1.27 (4 H, m) 0.73-0.88 (1 H, m)

Biological Assay Data

Coupled Nucleotide Exchange Assay:

Purified GDP-bound KRAS protein (aa 1-169), containing both G12C andC118A amino acid substitutions and an N-terminal His-tag, waspre-incubated with a compound dose-response titration for 2 hours inassay buffer (25 mM HEPES pH 7.4, 10 mM MgCl₂, and 0.01% Triton X-100).Following compound pre-incubation, purified SOS protein (aa 564-1049)and GTP (Roche 10106399001) were added to the assay wells and incubatedfor an additional hour. To determine the extent of inhibition ofSOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149),nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), andAlphaScreen glutathione donor beads (PerkinElmer 6765302) were added tothe assay wells and incubated for 10 minutes. The assay plates were thenread on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen®technology, and data were analyzed using a 4-parameter logistic model tocalculate IC₅₀ values.

Phospho-ERK1/2 MSD Assay:

MIA PaCa-2 (ATCC® CRL-1420™) and A549 (ATCC® CCL-185™) cells werecultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093)containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016).Sixteen hours prior to compound treatment, MIA PaCa-2 or A549 cells wereseeded in 96-well cell culture plates at a density of 25,000 cells/welland incubated at 37° C., 5% CO₂. A compound dose-response titration wasdiluted in growth media, added to appropriate wells of a cell cultureplate, and then incubated at 37° C., 5% CO₂ for 4 hours. Followingcompound treatment, cells were stimulated with 10 ng/mL EGF (Roche11376454001) for 10 min, washed with ice-cold Dulbecco'sphosphate-buffered saline, no Ca²⁺ or Mg²⁺ (ThermoFisher Scientific14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1%Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecylsulfate) containing protease inhibitors (Roche 4693132001) andphosphatase inhibitors (Roche 4906837001). Cell lysates were storedfrozen at −80° C. overnight. Phosphorylation of ERK1/2 incompound-treated lysates was assayed using Phospho-ERK1/2 Whole CellLysate kits (Meso Scale Discovery K151DWD) according to themanufacturer's protocol. Assay plates were read on a Meso ScaleDiscovery Sector Imager 6000, and data were analyzed using a 4-parameterlogistic model to calculate IC₅₀ values.

TABLE 15 Biochemical and cellular activity of compounds Coupled p-ERKIC₅₀ exchange (MIA PaCa-2, p-ERK IC₅₀ Ex. # IC₅₀ (μM) μM) (A549, μM) 1-1 0.355 2.55 >33.3  1-2 2.38 6.08 >100  1-3 0.610 3.84 >100 1-4 >10 >100 >100  1-5 6.66 — —  1-6 2.88 36.2 >100  1-7 0.2091.86 >100  1-8 0.894 6.07 >100  1-9 5.92 — —  1-10 0.381 1.09 11.1  1-110.695 8.2 >100  1-12 11.8 — —  1-13 >10 — —  1-14 1.78 5.03 >100  1-150.562 4.7 >100  1-16 0.492 4.83 >100  1-17 63.5 — —  1-18 0.3700.559 >33.3  1-19 0.297 1.33 >100  1-19-1 0.115 0.368 >100  1-19-25.10 >100 >100  1-20 0.683 4.99 >100  1-21 1.30 4.89 >100  1-22 >250 — — 1-23 >250 — —  1-28 2.20 — >100  2-1 0.341 1.89 3.7  2-2 12.7 — —  2-34.05 6.53 >100  2-4 >250 — —  2-5 0.684 5.46 3.7  2-5-1 0.308 1.14 >100 2-5-2 1.35 7.48 3.7  2-6 1.59 2.97 3.7  2-6-1 13.0 — —  2-6-2 1.25 1.293.7  2-7 1.08 3.87 >33.3  2-8 0.361 0.258 >100  2-9 0.301 0.747 >100 2-10 1.73 3.07 >100  3-1 0.266 3.23 >100  3-1-1 3.00 >100 >100  3-1-20.302 2.35 >100  3-2 >250 — —  3-3 11.3 — —  3-4 >250 — —  3-5 0.6935.26 3.7  3-6 1.05 11.8 >100  3-7 6.98 —  3-8 1.07 7.05 >100  3-9 3.379.25 >33.3  3-10 4.74 66.4 11.1  3-11 0.457 3.06 11.1  3-12 2.567.66 >100  3-13 6.49 — —  3-14 5.64 — —  3-15 4.03 20.1 >100  3-16 2.6021.3 >100  3-17 5.48 — —  3-18 2.60 >100 >100  3-19 0.954 2.03 >33.3 3-20 2.99 9.65 >100  3-21 32.0 — —  3-22 0.249 1.12 >33.3  3-23 4.6513.6 >100  3-24 9.07 23.7 >100  3-25 >250 — —  4-1 0.529 2.34 >100 4-2 >250 — —  4-3 >250 — —  4-4 >250 — —  4-5 >250 — —  4-6 0.63010.3 >100  4-7 125 — —  4-8 177 — —  4-9 >250 — —  5-1 0.875 2.86 >100 5-2 14.2 — —  5-3 14.2 — —  5-4 0.610 3.25 >100  5-5 0.341 2.53 >100 5-6 0.883 5.9 >100  5-7 0.815 3.79 >100  5-8 0.433 1.2 >33.3  5-9 0.1390.822 >100  6-1 0.537 1.3 3.7  6-2 5.31 — —  7-1 0.299 0.43 >100  7-20.180 0.222 >100  7-3 1.73 5.83 >100  8-1 0.542 0.211 62.3  8-1-1 0.1720.046 69.8  8-1-2 0.322 0.811 >100  8-2 0.152 0.050 >100  8-3 0.2830.061 >100  8-3-1 0.282 0.408 >100  8-3-2 0.340 0.028 >100  8-4 0.0950.017 >33.3  8-5 0.400 2.41 >100  8-6 0.100 0.012 69.9  8-6-2 0.1850.128 >100  8-6-1 0.066 0.01 >33.3  9-1 0.155 0.052 57.4  9-2 0.289 1.1174.4  9-3 0.113 0.035 66.1  9-4 0.198 0.023 13  9-5 1.33 3.92 >100  9-60.237 3.51 >100  9-7-2 — 0.232 62.0  9-7-1 — 0.023 14.9  9-9 0.147 0.13665.6  9-10 0.101 0.117 66.5  9-11 0.093 0.147 64  9-12 1.32 1.29 >100 9-13 0.306 0.078 12.8  9-14 0.129 0.344 >100 10-1 24.5 — — 10-2 1.9336.1 >100 10-3 1.10 9.33 >100 10-4 0.235 3.47 >100 10-5 0.297 3.41 >10010-6 1.20 6.07 >100 10-7 0.533 9.2 >100 10-8 1.34 12.9 >100 10-9 1.6833.6 >100 10-10 0.359 6.85 >100 10-11 0.516 14.7 >100 10-12 0.91222.6 >100 10-13 15.1 — — 11-1-1 0.231 0.247 42.9 11-1-2 0.151 0.016 21.711-2-1 0.219 0.054 10 11-2-2 0.256 0.006 26.4 12 3.34 25.9 >100 135.20 >100 >100 14 2.69 — — 15 2.56 — — 16 2.93 8.62 33.3 17-1 20.6 — —17-2 1.02 2.6 49.1 18-1 23.0 — — 18-2 0.760 >100 >100 18-3 24.6 — — 19-115.2 — — 19-2 1.62 4.69 3.7 19-3 115 — — 20 78.8 — — 21 9.41 — — 220.927 56.1 >100 23 3.29 3.21 >33.3 24 6.20 — — 25 0.251 0.786 >100 263.90 30.3 >100 27 1.28 12.8 >33.3 28 8.17 — — 29 3.76 >100 >100 30 7.5158 >100 31 123 — — 32 28.6 — — 33 103 — — 34 34.2 — — 35 8.01 79.7 >10036 39.8 — — 37 9.07 14.7 >100 38 0.484 1.39 >33.3

The present invention is described in connection with preferredembodiments. However, it should be appreciated that the invention is notlimited to the disclosed embodiments. It is understood that, given thedescription of the embodiments of the invention herein, variousmodifications can be made by a person skilled in the art. Suchmodifications are encompassed by the claims below.

What is claimed:
 1. A compound having a structure of formula (I)

wherein E¹ and E² are each independently N or CR¹; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl, and each R′ isindependently H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃ alkenyl, C₂₋₃alkynyl,aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; and R⁷ is Hor C₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; or a pharmaceutically acceptablesalt thereof.
 2. A compound having a structure of formula (I)

wherein E¹ and E² are each independently N or CR¹; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, aryl, or heteroaryl, or two R′ substituents, together withthe nitrogen atom to which they are attached, form a 3-7-membered ring;R³ is halo, C₁₋₃alkyl, C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₁₄cycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH; R⁵and R⁶ are each independently H, halo, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; and R⁷ is Hor C₁₋₆alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; or a pharmaceutically acceptablesalt thereof.
 3. A compound having a structure of formula (II)

wherein E¹ and E² are each independently N or CR¹; J is N, NR¹⁰, orCR¹⁰; M is N, NR¹³, or CR¹³;

is a single or double bond as necessary to give every atom its normalvalence; R¹ is independently H, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo,C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, andeach R′ is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, orC═NR⁸; R⁸ and R⁹ are each independently H, C₁₋₃alkyl, hydroxy,C₁₋₃alkoxy, cyano, nitro, or C₃₋₆cycloalkyl, or R⁸ and R⁹, takentogether with the carbon atom to which they are attached, can form a 3-6membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl, O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; and R¹³ is C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, or C₃₋₁₄cycloalkyl; or a pharmaceutically acceptablesalt thereof, with the proviso that (1) when J is NR¹⁰, M is N or CR¹³;(2) when M is NR¹³, J is N or CR¹⁰; (3) when J is CR¹⁰, M is N or NR¹³;and (4) when M is CR¹³, J is N or NR¹⁰.
 4. A compound having a structureof formula (II)

wherein E¹ and E² are each independently N or CR¹; J is N, NR¹⁰, orCR¹⁰; M is N, NR¹³, or CR¹³;

is a single or double bond as necessary to give every atom its normalvalence; R¹ is independently H, hydroxy, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, NH—C₁₋₄alkyl, N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo,C₁₋₆alkyl, C₁₋₆haloalkyl, OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, andeach R′ is independently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl,aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH; R⁵and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, orC═NR⁸; R⁸ and R⁹ are each independently H, C₁₋₃alkyl, hydroxy,C₁₋₃alkoxy, cyano, nitro, or C₃₋₆cycloalkyl, or R⁸ and R⁹, takentogether with the carbon atom to which they are attached, can form a 3-6membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl, O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; and R¹³ is C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkyleneamine, or C₃₋₁₄cycloalkyl; or a pharmaceutically acceptablesalt thereof, with the proviso that (1) when J is NR¹⁰, M is N or CR¹³;(2) when M is NR¹³, J is N or CR¹⁰; (3) when J is CR¹⁰, M is N or NR¹³;and (4) when M is CR¹³, J is N or NR¹⁰.
 5. The compound of claim 3 or 4,wherein when Q is C═O; and E¹ and E² are each CR¹; then either (1) R¹⁰is C₁₋₃alkylene-C₆₋₁₄aryl, C₁₋₃alkylene-C₃₋₁₄heteroaryl,C₀₋₃alkylene-C₃₋₈cycloalkyl, C₁₋₃alkylene-C₂₋₇heterocycloalkyl, or halo;or (2) R¹³ is C₁₋₃haloalkyl or C₃₋₅cycloalkyl.
 6. The compound of claim3 or 4, wherein J is NR¹⁰ and M is CR¹³.
 7. The compound of claim 3 or4, wherein J is CR¹⁰ and M is NR¹³.
 8. The compound of claim 3 or 4,wherein J is N and M is NR¹³.
 9. The compound of claim 3 or 4, wherein Jis NR¹⁰ and M is N.
 10. A compound having a structure of formula (III)or (III′):

wherein E¹ and E² are each independently N or CR¹; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, NH—C₁₋₄alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, orC═NR⁸; R⁸ and R⁹ are each independently H, C₁₋₆alkyl, hydroxy,C₁₋₆alkoxy, cyano, nitro, or C₃₋₁₄cycloalkyl, or R⁸ and R⁹, takentogether with the carbon atom to which they are attached, can form a 3-6membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl, O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.
 11. Acompound having a structure of formula (III) or (III′):

wherein E¹ and E² are each independently N or CR¹; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, NH—C₁₋₄alkyl,N(C₁₋₄alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₃alkyl,C₁₋₂haloalkyl, C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₁₄heterocycloalkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH; R⁵and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; Q is CR⁸R⁹, C═CR⁸R⁹, C═O, C═S, orC═NR⁸; R⁸ and R⁹ are each independently H, C₁₋₆alkyl, hydroxy,C₁₋₆alkoxy, cyano, nitro, or C₃₋₁₄cycloalkyl, or R⁸ and R⁹, takentogether with the carbon atom to which they are attached, can form a 3-6membered ring; R¹⁰ is C₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃ alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl, O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof. 12.The compound of claim 10 or 11, having a structure of formula (III). 13.The compound of claim 10 or 11, having a structure of formula (III′).14. The compound of any one of claims 3 to 12, wherein Q is C═O.
 15. Thecompound of any one of claims 3 to 12, wherein Q is C═S.
 16. Thecompound of any one of claims 3 to 12, wherein Q is C═NR⁸.
 17. Thecompound of claim 16, wherein R⁸ is C₁₋₂alkyl.
 18. The compound of anyone of claims 3 to 12, wherein Q is CR⁸R⁹.
 19. The compound of any oneof claims 3 to 12, wherein Q is C═CR⁸R⁹.
 20. The compound of claim 18 or19, wherein R⁸ and R⁹, taken together with the carbon atom to which theyare attached, form a 3-4 membered ring.
 21. The compound of claim 18 or19, wherein R⁸ is C₁₋₂alkyl, and R⁹ is H.
 22. A compound having astructure of formula (IV) or (IV′):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₂haloalkyl,C₁₋₃alkoxy, C₃₋₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, orheteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; R⁸ is H, C₁₋₃alkyl, hydroxy,C₁₋₃alkoxy, halo, cyano, nitro, C₃₋₁₄ cycloalkyl, or NR¹¹R¹²; R¹¹ andR¹² are each independently H, C₁₋₈alkyl, or C₃₋₁₄cycloalkyl; and R¹⁰ isC₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₂₋₁₄heteroaryl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₂₋₁₄heteroaryl,O—C₀₋₃alkylene-C₃₋₁₄ cycloalkyl, O—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, N—C₀₋₃alkylene-C₃₋₁₄ cycloalkyl,N—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, or C₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.
 23. Acompound having a structure of formula (IV) or (IV′):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₂haloalkyl,C₁₋₃alkoxy, C₃₋₁₄cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, orheteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH; R⁵and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; R⁸ is H, C₁₋₃alkyl, hydroxy,C₁₋₃alkoxy, halo, cyano, nitro, C₃₋₁₄ cycloalkyl, or NR¹¹R¹²; R¹¹ andR¹² are each independently H, C₁₋₈alkyl, or C₃₋₁₅cycloalkyl; and R¹⁰ isC₁₋₈alkyl, C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof. 24.The compound of claim 22 or 23, having a structure of formula (IV). 25.The compound of claim 22 or 23, having a structure of formula (IV′). 26.The compound of any one of claims 22 to 25, wherein E¹ and E² are eachCR¹, and R⁸ is hydroxy, halo, nitro, or C₃₋₆cycloalkyl.
 27. The compoundof any one of claims 22 to 25, wherein R⁸ is methyl.
 28. A compoundhaving a structure of formula (V):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₃₋₁₄cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅ alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅ alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH;R^(4′) is H, C₁₋₈alkyl, C₂₋₈alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl,C₁₋₆alkylene-OH, C₁₋₆ haloalkyl, cycloalklyl, heterocycloalkyl,C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄ heterocycloalkyl, aryl,heteroaryl, C₀₋₃alkylene-C₆₋₁₄aryl, or selected from

R⁵ and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; and R¹⁰ is C₁₋₈alkyl,C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, orC₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.
 29. Acompound having a structure of formula (V):

wherein E¹ and E² are each independently CR¹ or N; R¹ is independentlyH, hydroxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, NH—C₁₋₆alkyl,N(C₁₋₆alkyl)₂, cyano, or halo; R² is halo, C₁₋₆alkyl, C₁₋₆haloalkyl,OR′, N(R′)₂, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, aryl, heteroaryl,C₀₋₃alkylene-C₆₋₁₄aryl, or C₀₋₃alkylene-C₂₋₁₄heteroaryl, and each R′ isindependently H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₄cycloalkyl,C₂₋₁₄heterocycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, aryl, or heteroaryl, ortwo R′ substituents, together with the nitrogen atom to which they areattached, form a 3-7-membered ring; R³ is halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₃₋₁₄cycloalkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,aryl, or heteroaryl; R⁴ is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused,or spiro 6-11 membered ring; L is a bond, C₁₋₆alkylene, —O—C₀₋₅alkylene,—S—C₀₋₅alkylene, or —NH—C₀₋₅alkylene, and for C₂₋₆alkylene,—O—C₂₋₅alkylene, —S—C₂₋₅alkylene, and NH—C₂₋₅alkylene, one carbon atomof the alkylene group can optionally be replaced with O, S, or NH; R⁵and R⁶ are each independently H, halo, C₁₋₆alkyl, C₂-alkynyl, C₁₋₆alkylene-O—C₁₋₄alkyl, C₁₋₆alkylene-OH, C₁₋₆haloalkyl, C₁₋₆alkyleneamine,C₀₋₆ alkylene-amide, C₀₋₃alkylene-C(O)OH, C₀₋₃alkylene-C(O)OC₁₋₄alkyl,C₁₋₆ alkylene-O-aryl, C₀₋₃alkylene-C(O)C₁₋₄alkylene-OH, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl, C₀₋₃alkylene-C₆₋₁₄aryl,C₀₋₃alkylene-C₂₋₁₄heteroaryl, or cyano, or R⁵ and R⁶, together with theatoms to which they are attached, form a 4-6 membered ring; R⁷ is H orC₁₋₈alkyl, or R⁷ and R⁵, together with the atoms to which they areattached, form a 4-6 membered ring; and R¹⁰ is C₁₋₈alkyl,C₀₋₃alkylene-C₆₋₁₄aryl, C₀₋₃alkylene-C₃₋₁₄heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl, C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,C₁₋₆alkoxy, O—C₀₋₃ alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₃₋₁₄heteroaryl,O—C₀₋₃ alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₆₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl,NH—C₀₋₃ alkylene-C₂₋₁₄heterocycloalkyl, halo, cyano, or C₁₋₆alkylene-amine; or a pharmaceutically acceptable salt thereof.
 30. Thecompound of any one of claims 1 to 29, wherein each of E¹ and E² is CR¹.31. The compound of any one of claims 1, 2, 3, 4, 6 to 29 wherein E¹ isCR¹ and E² is N.
 32. The compound of any one of claims 1, 2, 3, 4, 6 to29, wherein E¹ is N and E² is CR¹.
 33. The compound of any one of claims1, 2, 3, 4, 6 to 29, wherein each of E¹ and E² is N.
 34. The compound ofany one of claims 1, 2, 3, 4, 6 to 33, wherein R¹⁰ is C₁₋₆alkyl, aryl,heteroaryl, C₃₋₁₄cycloalkyl, C₂₋₁₅heterocycloalkyl, C₁₋₄alkoxy,O—C₀₋₃alkylene-C₆₋₁₄aryl, O—C₀₋₃alkylene-C₂₋₁₄heteroaryl,O—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, O—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl,NH—C₁₋₈alkyl, N(C₁₋₈alkyl)₂, NH—C₀₋₃alkylene-C₃₋₁₄aryl,NH—C₀₋₃alkylene-C₂₋₁₄heteroaryl, NH—C₀₋₃alkylene-C₃₋₁₄cycloalkyl, orNH—C₀₋₃alkylene-C₂₋₁₄heterocycloalkyl.
 35. The compound of claim 28 or29, wherein E¹ and E² are each CR¹, and R¹⁰ is C₁₋₃alkylene-C₆₋₁₄aryl,C₁₋₃alkylene-C₂₋₁₄heteroaryl, C₀₋₃alkylene-C₃₋₁₄cycloalkyl,C₁₋₃alkylene-C₂₋₁₄heterocycloalkyl, or halo.
 36. The compound of any oneof claims 3 to 33, wherein R¹⁰ is C₁₋₈alkyl.
 37. The compound of any oneof claims 3 to 33, wherein R¹⁰ is C₀₋₃alkylene-C₆₋₁₄aryl.
 38. Thecompound of any one of claims 3 to 34, wherein R¹⁰ isC₀₋₃alkylene-C₃₋₁₄heteroaryl.
 39. The compound of any one of claims 3 to35, wherein R¹⁰ is C₀₋₃alkylene-C₃₋₁₄cycloalkyl.
 40. The compound of anyone of claims 3 to 24, 26, 27, and 30 to 33, wherein R¹⁰ isC₀₋₃alkylene-C₂₋₁₄heterocycloalkyl.
 41. The compound of any one ofclaims 3 to 33, wherein R¹⁰ is C₀₋₆alkylene-amine.
 42. The compound ofany one of claims 3 to 33, wherein R¹⁰ is selected from the groupconsisting of i-Pr, t-Bu, phenyl, benzyl, OCH₃, Cl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl,


43. The compound of any one of claims 3 to 33, wherein R¹⁰ comprisesortho-substituted aryl, ortho-substituted heteroaryl, or 2-substitutedcyclohexyl.
 44. The compound of claim 43, wherein R¹⁰ is selected fromthe group consisting


45. The compound of any one of claims 1 to 44, wherein R¹ is H.
 46. Thecompound of any one of claims 1 to 44, wherein R¹ is F.
 47. The compoundof any one of claims 1 to 44, wherein R¹ is methyl.
 48. The compound ofany one of claims 1 to 47, wherein R² is aryl.
 49. The compound of anyone of claims 1 to 47, wherein R² is heteroaryl.
 50. The compound of anyone of claims 1 to 47, wherein R² is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, phenyl,naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl,benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl,pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl,quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl,tetrahydroquinolinyl, or tetrahydroisoquinolinyl.
 51. The compound ofany one of claims 1 to 47, wherein R² is selected from the groupconsisting of Cl, Br, CF₃, OCH₃, OCH₂CH₃, phenyl,


52. The compound of any one of claims 1 to 47, wherein R² is selectedfrom the group consisting of bromine,


53. The compound of any one of claims 1 to 52, wherein R³ is halo. 54.The compound of claim 53, wherein R³ is Cl.
 55. The compound of any oneof claims 1 to 52, wherein R³ is C₁₋₂alkyl.
 56. The compound of claim55, wherein R³ is methyl.
 57. The compound of any one of claims 1 to 52,wherein R³ is C₁₋₂haloalkyl.
 58. The compound of claim 57, wherein R³ isCF₃.
 59. The compound of any one of claims 1 to 58, wherein R⁴ is


60. The compound of claim 59, wherein ring A is


61. The compound of any one of claims 1 to 58, wherein R⁴ is


62. The compound of claim 61, wherein ring A is selected from the groupconsisting of


63. The compound of any one of claims 1 to 58, wherein R⁴ is


64. The compound of any one of claims 1 to 58, wherein R⁴ is


65. The compound of claim 64, wherein ring A is selected from the groupconsisting of


66. The compound of any one of claims 59 to 65, wherein

is selected from the group consisting of


67. The compound of any one of claims 59 to 66, wherein L is a bond. 68.The compound of any one of claims 59 to 66, wherein L is C₁₋₂alkylene.69. The compound of claim 59, 60, 62, 63, or 66, wherein L is O.
 70. Thecompound of claim 59, 60, 62, 63, or 66, wherein L is S.
 71. Thecompound of claim 59, 61, 64, 65, or 66, wherein L is NH.
 72. Thecompound of any one of claims 1 to 59, 61, 63, 64 and 66, wherein ring Acomprises piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl.
 73. Thecompound of claim 72, wherein ring A comprises piperidinyl.
 74. Thecompound of any one of claims 1 to 59, 61, 63, 64 and 65, wherein R⁵ isH or halo.
 75. The compound of any one of claims 1 to 59, 61, 63, 64 and65, wherein R⁵ is H, Br, Cl, F, CN, CH₃, CF₃, CH₂Br, CH₂OH, CH₂CH₂OH,CH₂OCH₂phenyl, cyclopropyl, phenyl, CH₂phenyl, CH₂OCH₃, CH₂N(CH₃)₂,CH₂N(CH₂CH₃)₂, CH₂CO₂H, CH₂CO₂CH₃, CH₂NHC(O)CH₃, CH₂C(O)NHCH₃,CH₂OC(O)CH₃, or


76. The compound of any one of claims 1 to 65 and 67 to 75, wherein R⁶is H, C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₂alkyl, C₁₋₃alkylene-OH,C₁₋₃haloalkyl, C₁₋₃alkylene-amine, C₀₋₃alkylene-amide, C₀₋₁alkyleneC(O)OC₁₋₃alkyl, C₀₋₁alkylene-C₂₋₇heterocycloalkyl,C₀₋₁alkylene-C₃₋₈cycloalkyl, or C₀₋₃alkylene-C₆₋₁₄aryl.
 77. The compoundof claim 76, wherein R⁶ is C₁₋₃alkylene-amine or C₁₋₃ alkylene-amide andis selected from the group consisting of CH₂NH₂, CH(CH₃)NH₂,CH(CH₃)₂NH₂, CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂, CH₂NHCH₃, C(O)NHCH₃, C(O)N(CH₃)₂,CH₂C(O)NHphenyl, CH₂NHC(O)CH₃, CH₂NHCH₂CH₂OH, CH₂NHCH₂CO₂H,CH₂NH(CH₃)CH₂CO₂CH₃, CH₂NHCH₂CH₂OCH₃, CH₂NH(CH₃)CH₂CH₂OCH₃,CH₂NH(CH₃)CH₂C(O)N(CH₃)₂, CH₂NH(CH₃)CH₂C(O)NHCH₃, CH₂NMe₂,CH₂NH(CH₃)CH₂CH₂OH, CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃, CH₂NHCH₂CHF₂,CH₂NHCH₂CH₃,


78. The compound of any one of claims 1 to 65 and 67 to 75, wherein R⁶is phenyl, cyclopropyl, CH₃, CF₃, CH₂CH₃, CH₂NH₂, CH(CH₃)NH₂,CH(CH₃)₂NH₂, CH₂C₁, CH₂Br, CH₂OCH₃, CH₂Ophenyl, CH₂OH, CO₂H, CO₂CH₂CH₃,CH₂CO₂H, CH₂CH₂NH₂, CH₂CH₂OH, CH₂CH₂N(CH₃)₂, CH₂NHCH₃, C(O)NHCH₃,C(O)N(CH₃)₂, CH₂C(O)NHphenyl, CH₂CHF₂, CH₂F, CHF₂, CH₂NHC(O)CH₃,CH₂NHCH₂CH₂OH, CH₂NHCH₂CO₂H, CH₂NH(CH₃)CH₂CO₂CH₃, CH₂NHCH₂CH₂OCH₃,CH₂NH(CH₃)CH₂CH₂OCH₃, CH₂NH(CH₃)CH₂C(O)N(CH₃)₂, CH₂NH(CH₃)CH₂C(O)NHCH₃,CH₂CH₂CCH, CH₂NMe₂, CH₂NH(CH₃)CH₂CH₂OH, CH₂NH(CH₃)CH₂CH₂F, CH₂N⁺(CH₃)₃,CH₂NHCH₂CHF₂, CH₂NHCH₂CH₃,


79. The compound of any one of claims 1 to 65 and 67 to 73, wherein R⁵and R⁶ together are


80. The compound of any one of claims 1 to 65 and 67 to 73, wherein eachof R⁵ and R⁶ is H.
 81. The compound of any one of claims 1 to 58 and 63to 80, wherein R⁷ is H.
 82. The compound of any one of claims 1 to 58and 63 to 80, wherein R⁷ is methyl.
 83. The compound of any one ofclaims 1 to 58, 63 to 65, 67-73 and 76 to 78, wherein R⁷ and R⁵ togetherare —CH₂— or —C(O)CH₂—.
 84. The compound of any one of claims 1 to 58,wherein R⁴ is selected from the group consisting of


85. A compound as recited in Table
 1. 86. The compound of any one ofclaims 1 to 85 in the form of a pharmaceutically acceptable salt.
 87. Apharmaceutical formulation comprising the compound of any one of claims1 to 86 and a pharmaceutically acceptable excipient.
 88. A method ofinhibiting KRAS G12C in a cell, comprising contacting the cell with thecompound of any one of claims 1 to 86 or the composition of claim 87.89. A method of treating cancer in a subject comprising administering tothe subject a therapeutically effective amount of the compound of anyone of claims 1 to 86 or the composition of claim
 87. 90. The method ofclaim 89, wherein the cancer is lung cancer, pancreatic cancer, orcolorectal cancer.
 91. A compound having a structure selected from:


92. The compounds of claim 91 in the form of a pharmaceuticallyacceptable salt.
 93. A pharmaceutical formulation comprising thecompounds of claim 91 or 92 and a pharmaceutically acceptable excipient.